JP2023553810A - Antiviral activity of VPS34 inhibitors - Google Patents

Abstract

Described in part herein is a method of treating a viral infection, such as a coronavirus infection, in a patient in need thereof, the method comprising administering a VPS34 inhibitor to the patient.

Description

Related applications

(cross reference)
This application claims priority to U.S. Provisional Application No. 63/118,514, filed November 25, 2020, which is incorporated herein by reference in its entirety.

There is an unmet medical need to identify drugs for therapeutic treatment of SARS CoV-2 and related coronaviruses. +RNA viruses, including coronaviruses, have been reported to require the formation of double membrane vesicles during the viral replication process. These double membrane vesicles are similar to autophagosomes. The formation of these vesicles is important for viral replication because +RNA viruses, including coronaviruses, have specialized nonstructural proteins that initiate the formation of these double-membrane vesicles during infection of host cells. Further support is provided by the finding that NSP6 encodes NSP6. These vesicles are required during viral replication to protect the double-stranded viral RNA from host cell RNAases that degrade the viral RNA and inhibit viral replication. siRNA interference with LC-3, a protein essential for autophagosome formation, has been demonstrated to inhibit coronavirus replication. Additionally, double-labeling studies have demonstrated colocalization of LC-3 with viral replicase proteins nsp8, nsp2, and nsp3. Therefore, evidence indicates that these double-membrane vesicles are required for viral replication of coronaviruses, including SARS CoV-2.

A novel therapeutic avenue for patients with COVID-19 or other coronavirus infections is to target and block the formation of these double-membrane vesicles required for viral replication. Genetic studies have shown that some +RNA viruses require ULK kinase to initiate the formation of infected cell autophagosomes, and other +RNA viruses require the VPS34 kinase to initiate the formation of infected cell autophagosomes. It has been shown that It was recently disclosed that the VPS34 kinase is required for the formation of double membrane vesicles in SARS CoV-2 and related viruses. Packaging of coronavirus progeny within infected cells by double-membrane vesicles allows spread of the virus from infected cells and can also cause infection of other cells. During this process, protection of the coronavirus containing SARS CoV-2 within double-membrane vesicles may shield the spread of the virus from the immune system. VPS34 inhibitors therefore offer the potential to inhibit viral replication of coronaviruses, including SARS CoV-2.

In addition to playing a role in the formation of double-membrane autophagosomes, VPS34 kinase also plays an essential role in the associated endosomal pathway that forms double-membrane vesicles. The endosomal pathway may also play a role in virus entry into host cells infected with coronaviruses, including SAR COV-2. Endosomes have also been demonstrated to play a role in viral transport following viral entry. Therefore, inhibitors of VPS34 kinase may inhibit several steps during the coronavirus replication cycle: 1) inhibition of viral entry; 2) inhibition of post-entry viral transport; and 3) viral replicase complex. inhibition of the body.

Described herein are methods of treating a viral infection, inhibiting viral transmission, inhibiting viral replication, minimizing expression of viral proteins, or inhibiting viral release using a VPS34 inhibitor. is partially provided.

For example, in one embodiment, a method of alleviating or treating a viral infection in a patient in need thereof, comprising:

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R ¹ is phenyl and monocyclic 5 ~6-membered heteroaryl, each of phenyl and monocyclic 5-6 membered heteroaryl being halogen, C ₁ -C ₆ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ one or more independently selected from the group consisting of -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, amino, N-C ₁ -C ₃ alkylamino and N,N- _{diC 1} -C ₃ alkylamino R ² is selected from the group consisting of H, C ₁ -C ₃ haloalkyl, and C ₁ -C 3 alkyl; R ³ is A, phenyl, and monocyclic heteroaryl; each phenyl and heteroaryl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of R ⁴ , R ⁵ , R ⁶ , and R ⁷ . each of R ⁴ , R ⁵ , R ⁶ , and R ⁷ is halogen, C ₁ -C ₆ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C From the group consisting of ₁ -C ₆ haloalkoxy, azetidine, amino, N-C ₁ -C ₃ alkylamino, N,N-diC ₁ -C ₃ alkylamino, NHSO ₂ R ⁸ , SO ₂ R ⁹ , and hydroxy independently selected; R ⁸ is selected from C ₁ -C ₃ haloalkyl and C ₁ -C ₃ alkyl; each R ⁹ is selected from R ¹⁰ , C ₁ -C ₆ alkyl, amino, N-C ₁ -C independently selected from the group consisting of _{C 1 -C} 3 alkylamino, N,N-diC 1 -C ₃ alkylamino, and C ₁ -C ₃ alkoxyC 1 -C ₃ alkyl, _{C 1 -C 6} alkyl and C ₁ - Each of C ₃ alkoxyC ₁ -C ₃ alkyl is optionally substituted with one occurrence of R ¹⁰ and each _of C ₁ -C ₆ alkyl and C _{1 -C 3} alkyl is halogen each R ¹⁰ is independently selected from the group consisting of phenyl, benzyl, monocyclic heteroaryl, C ₃ -C ₆ cycloalkyl, and heterocyclyl; Each of phenyl, benzyl, monocyclic heteroaryl, C ₃ -C ₆ cycloalkyl, and heterocyclyl is optionally substituted with one or more occurrences of R ¹¹ ; each R ¹¹ is halogen, C ₁ -C _3- haloalkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₃ alkyl, amino, N-C ₁ -C ₃ alkylamino, N,N-diC ₁ -C ₃ alkylamino, and C ₁ -C ₃ alkoxy independently selected from the group consisting of C ₁ -C ₃ alkyl; A is

R ¹² is H, halogen, COR ¹³ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl, C ₁ -C ₆ alkoxy, C selected from the group consisting of ₃ - _C6 cycloalkyl, _C1 - _C3 cyanoalkyl, and _C1 - _C3 haloalkyl; ^R13 is _C1 - _C3 alkoxy, N- _C1 - _C3 alkylamino, selected from the group consisting of N,N-diC ₁ -C ₃ alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl; Y is CH ₂ , S, SO, SO ₂ , NR ¹⁴ , NCOR ⁹ , NCOOR ¹⁵ , NSO ₂ R ⁹ , NCOCH ₂ R ⁹ , O, and a bond; R ¹⁴ is H, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl , C ₁ -C ₃ alkyl, and C ₃ -C ₆ cycloalkyl; R ¹⁵ is selected from R ¹⁰ , C ₁ -C ₆ alkyl, and C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl; , C ₁ -C ₆ alkyl and C ₁ -C ₃ alkoxy each of C ₁ -C ₃ alkyl is optionally substituted with one occurrence of R ¹⁰ , C ₁ -C ₆ alkyl and C ₁ -C ₃ alkoxy Each of the C ₁ -C ₃ alkyls is optionally substituted with one or more independent occurrences of halogen; Z is selected from CH and N, methods are described herein.

In one embodiment, a method of inhibiting viral transmission, inhibiting viral entry, inhibiting viral replication, minimizing expression of viral proteins, or inhibiting viral release, the method comprising formula I administering to a patient suffering from a virus a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; contacting the virus-infected cell with an effective amount of a salt, stereoisomer, or tautomer acceptable to the compound of formula I:

where R ¹ is selected from phenyl and monocyclic 5-6 membered heteroaryl, each of phenyl and monocyclic 5-6 membered heteroaryl is halogen, C ₁ -C ₆ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, amino, N-C ₁ -C ₃ alkylamino and N,N-diC ₁ - optionally substituted with one or more substituents independently selected from the group consisting of C ₃ alkylamino; R ² is from the group consisting of H, C ₁ -C ₃ haloalkyl, and C ₁ -C 3 alkyl R ³ is selected from the group consisting of A, phenyl, and monocyclic heteroaryl, each phenyl and heteroaryl being independently selected from the group consisting of R ⁴ , R ⁵ , R ⁶ , and R ⁷ ; each of R ⁴ , R ⁵ , R ⁶ , and R ⁷ is halogen, C ₁ -C ₆ alkyl, C ₃ -C ₄ cyclo Alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, azetidine, amino, N-C ₁ -C ₃ alkylamino, N,N-diC ₁ -C ₃ alkylamino , NHSO ₂ R ⁸ , SO ₂ R ⁹ , and hydroxy; R ⁸ is selected from C ₁ -C ₃ haloalkyl and C ₁ -C ₃ alkyl; each R ⁹ is R ¹⁰ , C ₁ -C ₆ alkyl, amino, N-C ₁ -C ₃ alkylamino, N,N-diC ₁ -C ₃ alkylamino, and C _{1 -C 3} alkoxyC ₁ -C ₃ alkyl each of C ₁ -C ₆ alkyl and C ₁ -C 3 alkoxyC 1 -C ₃ alkyl independently selected from C 1 -C ₆ alkyl and C _{1 -C 6} alkyl optionally substituted with one occurrence of R ¹⁰ Each of C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl is optionally substituted with one or more independent occurrences of halogen; each R ¹⁰ is phenyl, benzyl, monocyclic heteroaryl, C ₃ - independently selected from the group consisting of C ₆ cycloalkyl, and heterocyclyl, each of phenyl, benzyl, monocyclic heteroaryl, C ₃ -C ₆ cycloalkyl, and heterocyclyl at one or more occurrences of R ¹¹ optionally substituted; each R ¹¹ is halogen, C ₁ -C ₃ haloalkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₃ alkyl, amino, N-C ₁ -C ₃ alkylamino, N,N -diC ₁ -C ₃ alkylamino, and C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl;

R ¹² is H, halogen, COR ¹³ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl, C ₁ -C ₆ alkoxy, C selected from the group consisting of ₃ - _C6 cycloalkyl, _C1 - _C3 cyanoalkyl, and _C1 - _C3 haloalkyl; ^R13 is _C1 - _C3 alkoxy, N- _C1 - _C3 alkylamino, selected from the group consisting of N,N-diC ₁ -C ₃ alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl; Y is CH ₂ , S, SO, SO ₂ , NR ¹⁴ , NCOR ⁹ , NCOOR ¹⁵ , NSO ₂ R ⁹ , NCOCH ₂ R ⁹ , O, and a bond; R ¹⁴ is H, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl , C ₁ -C ₃ alkyl, and C ₃ -C ₆ cycloalkyl; R ¹⁵ is selected from R ¹⁰ , C ₁ -C ₆ alkyl, and C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl; , C ₁ -C ₆ alkyl and C ₁ -C ₃ alkoxy each of C ₁ -C ₃ alkyl is optionally substituted with one occurrence of R ¹⁰ , C ₁ -C ₆ alkyl and C ₁ -C ₃ alkoxy Methods are described herein in which each C ₁ -C ₃ alkyl is optionally substituted with one or more independent occurrences of halogen; Z is selected from CH and N.

In one embodiment, a method of treating a Coronaviridae infection in a patient in need thereof, comprising:

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R ¹ is phenyl and monocyclic 5 ~6-membered heteroaryl, each of phenyl and monocyclic 5-6 membered heteroaryl being halogen, C ₁ -C ₆ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ one or more independently selected from the group consisting of -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, amino, N-C ₁ -C ₃ alkylamino and N,N- _{diC 1} -C ₃ alkylamino R ² is selected from the group consisting of H, C ₁ -C ₃ haloalkyl, and C ₁ -C 3 alkyl; R ³ is A, phenyl, and monocyclic heteroaryl; each phenyl and heteroaryl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of R ⁴ , R ⁵ , R ⁶ , and R ⁷ . each of R ⁴ , R ⁵ , R ⁶ , and R ⁷ is halogen, C ₁ -C ₆ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C From the group consisting of ₁ -C ₆ haloalkoxy, azetidine, amino, N-C ₁ -C ₃ alkylamino, N,N-diC ₁ -C ₃ alkylamino, NHSO ₂ R ⁸ , SO ₂ R ⁹ , and hydroxy independently selected; R ⁸ is selected from C ₁ -C ₃ haloalkyl and C ₁ -C ₃ alkyl; each R ⁹ is selected from R ¹⁰ , C ₁ -C ₆ alkyl, amino, N-C ₁ -C independently selected from the group consisting of _{C 1 -C} 3 alkylamino, N,N-diC 1 -C ₃ alkylamino, and C ₁ -C ₃ alkoxyC 1 -C ₃ alkyl, _{C 1 -C 6} alkyl and C ₁ - Each of C ₃ alkoxyC ₁ -C ₃ alkyl is optionally substituted with one occurrence of R ¹⁰ and each _of C ₁ -C ₆ alkyl and C _{1 -C 3} alkyl is halogen each R ¹⁰ is independently selected from the group consisting of phenyl, benzyl, monocyclic heteroaryl, C ₃ -C ₆ cycloalkyl, and heterocyclyl; Each of phenyl, benzyl, monocyclic heteroaryl, C ₃ -C ₆ cycloalkyl, and heterocyclyl is optionally substituted with one or more occurrences of R ¹¹ ; each R ¹¹ is halogen, C ₁ -C _3- haloalkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₃ alkyl, amino, N-C ₁ -C ₃ alkylamino, N,N-diC ₁ -C ₃ alkylamino, and C ₁ -C ₃ alkoxy independently selected from the group consisting of C ₁ -C ₃ alkyl; A is

R ¹² is H, halogen, COR ¹³ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl, C ₁ -C ₆ alkoxy, C selected from the group consisting of ₃ - _C6 cycloalkyl, _C1 - _C3 cyanoalkyl, and _C1 - _C3 haloalkyl; ^R13 is _C1 - _C3 alkoxy, N- _C1 - _C3 alkylamino, selected from the group consisting of N,N-diC ₁ -C ₃ alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl; Y is CH ₂ , S, SO, SO ₂ , NR ¹⁴ , NCOR ⁹ , NCOOR ¹⁵ , NSO ₂ R ⁹ , NCOCH ₂ R ⁹ , O, and a bond; R ¹⁴ is H, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl , C ₁ -C ₃ alkyl, and C ₃ -C ₆ cycloalkyl; R ¹⁵ is selected from R ¹⁰ , C ₁ -C ₆ alkyl, and C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl; , C ₁ -C ₆ alkyl and C ₁ -C ₃ alkoxy each of C ₁ -C ₃ alkyl is optionally substituted with one occurrence of R ¹⁰ , C ₁ -C ₆ alkyl and C ₁ -C ₃ alkoxy Methods are described herein in which each C ₁ -C ₃ alkyl is optionally substituted with one or more independent occurrences of halogen; Z is selected from CH and N.

The definitions provided in this application are intended to clarify terms used throughout this application. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter herein belongs. As used in this specification and the appended claims, unless otherwise specified, the following terms have the meanings indicated to facilitate an understanding of this disclosure. When a substituent is listed without indicating the atom to which the substituent is attached to the remainder of the compound of a given formula, the substituent is May be combined. Combinations of substituents, substituent positions and/or variables are permissible only if such combinations result in stable compounds. The substituents and substitution patterns on the compounds of this disclosure are chemically stable compounds that can be easily synthesized from readily available starting materials by techniques known in the art, and by methods described below. It is understood that the compound can be selected by one of ordinary skill in the art to yield the compound. It is understood that when a substituent is itself substituted with multiple groups, these multiple groups may be on the same carbon or on different carbons as long as a stable structure is obtained.

As used herein, "Compound 1" refers to a compound having the following structure.

As used herein, "Compound 2" refers to a compound having the following structure.

As used herein, "Compound 3" refers to a compound having the following structure.

As used herein, "Compound 4" refers to a compound having the following structure.

As used herein, the term "C ₁ -C ₆ alkyl" refers to both straight and branched chain saturated hydrocarbon groups having 1 to 6 carbon atoms. Examples of C ₁ -C ₆ alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 4-methyl-butyl, n- Examples include hexyl and 2-ethyl-butyl groups. Among unbranched C ₁ -C ₆ alkyl groups, typical are methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl groups. Among the branched alkyl groups, mention may be made of the iso-propyl, iso-butyl, sec-butyl, t-butyl, 4-methyl-butyl and 2-ethyl-butyl groups.

As used herein, the term "C ₁ -C ₃ alkyl" refers to both straight and branched chain saturated hydrocarbon groups having 1 to 3 carbon atoms. Examples of C ₁ -C ₃ alkyl groups include methyl, ethyl, n-propyl and isopropyl groups.

As used herein, the term "C ₁ -C ₆ alkoxy" refers to the group O-alkyl, and "C ₁ -C ₆ alkyl" is used as described above. Examples of C ₁ -C ₆ alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, n-hexoxy, 3-methyl-butoxy groups.

As used herein, the term "C ₁ -C ₃ alkoxy" refers to the group O-alkyl, and "C ₁ -C ₃ alkyl" is used as described above. Examples of C ₁ -C ₃ alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy and n-propoxy.

As used herein, the term "C ₁ -C ₆ haloalkyl" having 1 to 6 carbon atoms, with one to all hydrogens replaced with halogen of another or the same type; It refers to both straight chain and branched saturated hydrocarbon groups. Examples of C ₁ -C ₆ haloalkyl groups include methyl substituted with 1 to 3 halogen atoms, ethyl substituted with 1 to 5 halogen atoms, n substituted with 1 to 7 halogen atoms -propyl or iso-propyl, n-butyl or iso-butyl substituted with 1 to 9 halogen atoms, and sec-butyl or t-butyl groups substituted with 1 to 9 halogen atoms.

As used herein, the term "C ₁ -C ₃ haloalkyl" refers to a straight chain having from 1 to 3 carbon atoms in which from 1 to all hydrogens are replaced with halogens of another or the same type. and branched saturated hydrocarbon groups. Examples of C ₁ -C ₃ haloalkyl groups include methyl substituted with 1 to 3 halogen atoms, ethyl substituted with 1 to 5 halogen atoms, and Mention may be made of n-propyl or iso-propyl.

As used herein, the term "C ₁ -C ₃ haloalkoxy" has 1 to 3 carbon atoms, and one to all hydrogen atoms are replaced with halogen atoms of another or the same type. refers to both straight-chain and branched saturated alkoxy groups. Examples of C ₁ -C ₃ haloalkoxy groups include methoxy substituted with 1 to 3 halogen atoms, ethoxy substituted with 1 to 5 halogen atoms, and ethoxy substituted with 1 to 7 halogen atoms. and n-propoxy or iso-propoxy.

As used herein, the term "C ₁ -C3 fluoroalkyl" refers to straight and branched chains having from 1 to 3 carbon atoms with one to all hydrogen atoms replaced with fluorine atoms. It means both saturated hydrocarbon groups. Examples of C1-C3 fluoroalkyl groups include methyl substituted with 1 to 3 fluorine atoms, ethyl substituted with 1 to 5 fluorine atoms, and n substituted with 1 to 7 fluorine atoms. -propyl or iso-propyl.

As used herein, the term "C ₁ -C ₃ fluorooalkoxy" refers to straight and branched chains having from 1 to 3 carbon atoms with one to all hydrogen atoms replaced with fluorine atoms. Refers to both chain saturated alkoxy groups. Examples of C ₁ -C ₃ fluoroalkoxy groups include methoxy substituted with 1 to 3 fluorine atoms, ethoxy substituted with 1 to 5 fluorine atoms, and ethoxy substituted with 1 to 7 fluorine atoms. and n-propoxy or iso-propoxy.

As used herein, the term "C ₃ -C ₆ cycloalkyl" refers to a cyclic saturated hydrocarbon group having from 3 to 6 carbon atoms. Examples of C ₃ -C ₆ cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

As used herein, the term "C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl" has 1 to 3 carbon atoms substituted with an alkoxy group having 1 to 3 carbon atoms. It refers to both straight chain and branched saturated hydrocarbon groups. Examples of C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl groups are shown below.

As used herein, the term "C ₁ -C ₃ cyanoalkyl" refers to straight and branched cyano (CN) groups having from 1 to 3 carbon atoms, including the carbon atoms that are part of the cyano group. It means both derivatives. Examples of C ₁ -C ₃ cyanoalkyl groups are shown below.

As used herein, the term "halogen" means fluorine, chlorine, bromine or the element.

As used herein, the term "aryl" refers to a monocyclic or bicyclic aromatic carbocyclic group. Examples of aryl groups include phenyl and naphthyl. The A naphthyl group may be bonded via the 1 or 2 position. In a bicyclic aryl, one of the rings may be partially saturated. Examples of such groups include indanyl and tetrahydronaphthyl.

As used herein, the term "monocyclic aryl" refers to a monocyclic aromatic carbocyclic group. An example of a monocyclic aryl group is phenyl.

As used herein, the term "heteroaryl" means one to three of the carbon atoms are replaced with one or more heteroatoms independently selected from nitrogen, oxygen or sulfur. means a monocyclic or bicyclic aromatic group of carbon atoms. In a bicyclic aryl, one of the rings may be partially saturated. Examples of such groups include indolinyl, dihydrobenzofuran and 1,3-benzodioxolyl.

As used herein, the term "monocyclic heteroaryl" means one to three of the carbon atoms are replaced with one or more heteroatoms independently selected from nitrogen, oxygen, or sulfur. means a monocyclic aromatic group of carbon atoms.

Examples of monocyclic heteroaryl groups include, but are not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl. , and pyrimidinyl.

Examples of bicyclic heteroaryl groups include, but are not limited to, quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, quinolinyl, benzofuryl, indolyl, indazolyl, benzothiazolyl, pyri Dopyrimidinyl, and isoquinolinyl.

As used herein, the term "heterocyclyl" refers to a carbon having one to three of its carbon atoms replaced with one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. means a cyclic group of atoms. Examples of heterocyclyl groups include, but are not limited to, tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and dioxanyl.

"Combination therapy" is a treatment that involves administering two or more therapeutic agents, e.g., a compound of Formula I and an antibiotic, a viral protease inhibitor, or an antiviral nucleoside antimetabolite to a patient in need thereof. It is.

As used herein, "disease," "disorder," and "condition" are used interchangeably.

"Individual," "patient," or "subject" are used interchangeably herein and include mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, Includes any animal, including horses, or primates, and most preferably humans. The compounds described herein can be administered to mammals, such as humans, but also animals in need of veterinary treatment, such as companion animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, sheep, etc.). , pigs, horses, etc.) and other mammals such as laboratory animals (e.g., rats, mice, guinea pigs, etc.).

"Pharmaceutically or pharmacologically acceptable" includes molecular entities and compositions that do not produce adverse, allergic, or other adverse reactions when appropriately administered to animals or humans. For human administration, formulations must meet sterility, pyrogenicity, and general safety and purity standards as required by the FDA Office of Biologics standards.

As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to all solvents, dispersion media, Refers to coatings, isotonic and absorption delaying agents, etc. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds that provide complementary, additional, or enhanced therapeutic functions.

As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound disclosed herein formulated with one or more pharmaceutically acceptable carriers. Point.

As used herein, the term "pharmaceutically acceptable salt" refers to salts of acidic or basic groups that may be present in compounds used in compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds include non-toxic acid addition salts, i.e. malate, oxalate, chloride, bromide, iodide. nitrates, sulfates, bisulfates, phosphates, acid phosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, oleates, tannates, pantothenes Acid salts, bitartrates, ascorbates, succinates, maleates, gentisinates, fumarates, gluconates, glucaronates, saccharides, formates, benzoates, glutamic acids salts, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e. 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Forms salts containing pharmacologically acceptable anions, including but not limited to. Compounds included in the present compositions that are acidic in nature are capable of forming base salts with a variety of pharmacologically acceptable cations. Examples of such salts include alkali or alkaline earth metal salts, especially calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds included in the present compositions that contain basic or acidic moieties may also form pharmaceutically acceptable salts with various amino acids. Compounds of the present disclosure may contain both acidic and basic groups, eg, one amino group and one carboxylic acid group. In such cases, the compound may exist as an acid addition salt, zwitterion, or base salt.

Compounds of the present disclosure may contain one or more chiral centers and therefore exist as stereoisomers. As used herein, the term "stereoisomer" consists of all enantiomers or diastereomers. These compounds may be designated by the symbols "(+)", "(-)", "R", or "S", depending on the configuration of substituents around the stereogenic carbon atom, One of ordinary skill in the art will recognize that a structure may imply a chiral center. The compounds described herein encompass various stereoisomers of these compounds and mixtures thereof. Although mixtures of enantiomers or diastereomers may be designated as "(±)" in nomenclature, those skilled in the art will recognize that the structure may imply chiral centers.

As used herein, the term "therapeutically effective amount" refers to the biological response of a tissue, system, or animal (e.g., mammal or human) sought by a researcher, veterinarian, physician, or other clinician. or refers to the amount of the compound of interest that elicits a medical response. The compounds described herein are administered in a therapeutically effective amount to treat a disorder.

As used herein, "treating" includes any effect, such as attenuating, reducing, modulating, or eliminating, that results in amelioration of a condition, disease, disorder, and the like.

The present disclosure also provides that one or more of the atoms listed herein except that one or more atoms are replaced by an atom having an atomic mass or mass number that differs from that normally found in nature. Includes isotopically labeled compounds that are identical. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ Examples include N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ Cl. For example, compounds of the present disclosure may have one or more H atoms replaced with deuterium.

Individual enantiomers and diastereomers of the compounds of this disclosure may be prepared synthetically from commercially available starting materials containing asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those skilled in the art. may be prepared. These resolution methods include (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography, and separation of the optically pure product from the auxiliary. (2) salt formation using an optically active resolving agent, (3) direct separation of a mixture of optical enantiomers on a chiral liquid chromatography column, or (4) kinetically using stereoselective chemical or enzymatic reagents. exemplified by division. Racemic mixtures can also be resolved into their component enantiomers by well-known methods such as chiral phase liquid chromatography or crystallization of the compounds in chiral solvents. Stereoselective synthesis, which is a chemical or enzymatic reaction in which a single reactant forms a unequal mixture of stereoisomers during the creation of a new stereocenter or the conversion of an existing stereocenter, is well known in the art. It is. Stereoselective synthesis encompasses both enantio- and diastereoselective transformations and may involve the use of chiral auxiliaries. See, eg, Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

Compounds In one embodiment, Formula I:

Described herein are compounds of or pharmaceutically acceptable salts, stereoisomers, or tautomers thereof, wherein R ¹ is selected from phenyl and monocyclic 5-6 membered heteroaryl. , phenyl and monocyclic 5-6 membered heteroaryl each represent halogen, C ₁ -C ₆ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ - optionally substituted with one or more substituents independently selected from the group consisting of C ₆ haloalkoxy, amino, N-C ₁ -C ₃ alkylamino and N,N-diC ₁ -C ₃ alkylamino R ² is selected from the group consisting of H, C ₁ -C ₃ haloalkyl, and C ₁ -C 3 alkyl; R ³ is selected from the group consisting of A, phenyl, and monocyclic heteroaryl, phenyl and heteroaryl is optionally substituted with one or more occurrences of substituents independently selected from ^the group consisting of ^{R 4} , R ⁵ , R ⁶ , and R ⁷ ; Each of R ⁶ and R ⁷ is halogen, C ₁ -C ₆ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, azetidine , amino, N-C ₁ -C ₃ alkylamino, N ^, N-diC ₁ -C ₃ alkylamino, NHSO ₂ R ⁸ , SO ₂ R ⁹ , and hydroxy; is selected from C ₁ -C ₃ haloalkyl and _C 1 -C ₃ alkyl; each R ⁹ is R ¹⁰ , C ₁ -C ₆ alkyl, amino, N-C ₁ -C ₃ alkylamino, N,N- independently selected from the group consisting of diC ₁ -C ₃ alkylamino, and C ₁ -C ₃ alkoxyC 1 -C ₃ alkyl, C _{1 -C 6} alkyl and C ₁ -C ₃ alkoxyC ₁ -C ₃ Each alkyl is optionally substituted with one occurrence of R ¹⁰ and each of C ₁ -C ₆ alkyl and C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl is substituted with one or more independent occurrences of halogen. each R ¹⁰ is independently selected from the group consisting of phenyl, benzyl, monocyclic heteroaryl, C ₃ -C ₆ cycloalkyl, and heterocyclyl; Each of aryl, C ₃ -C ₆ cycloalkyl, and heterocyclyl is optionally substituted with one or more occurrences of R ¹¹ ; each R ¹¹ is halogen, C ₁ -C ₃ haloalkyl, C ₃ -C ₄ Consisting of cycloalkyl, C ₁ -C ₃ alkyl, amino, N-C ₁ -C ₃ alkylamino, N,N-diC ₁ -C ₃ alkylamino, and C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl independently selected from the group; A is

R ¹² is H, halogen, COR ¹³ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl, C ₁ -C ₆ alkoxy, C selected from the group consisting of ₃ - _C6 cycloalkyl, _C1 - _C3 cyanoalkyl, and _C1 - _C3 haloalkyl; ^R13 is _C1 - _C3 alkoxy, N- _C1 - _C3 alkylamino, selected from the group consisting of N,N-diC ₁ -C ₃ alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl; Y is CH ₂ , S, SO, SO ₂ , NR ¹⁴ , NCOR ⁹ , NCOOR ¹⁵ , NSO ₂ R ⁹ , NCOCH ₂ R ⁹ , O, and a bond; R ¹⁴ is H, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl , C ₁ -C ₃ alkyl, and C ₃ -C ₆ cycloalkyl; R ¹⁵ is selected from R ¹⁰ , C ₁ -C ₆ alkyl, and C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl; , C ₁ -C ₆ alkyl and C ₁ -C ₃ alkoxy each of C ₁ -C ₃ alkyl is optionally substituted with one occurrence of R ¹⁰ , C ₁ -C ₆ alkyl and C ₁ -C ₃ alkoxy Each C ₁ -C ₃ alkyl is optionally substituted with one or more independent occurrences of halogen; Z is selected from CH and N.

In some embodiments, R ¹ is a monocyclic 5-6 membered heteroaryl. In some embodiments, R ² is selected from H and C ₁ -C ₃ alkyl. In some embodiments, R ³ is selected from phenyl and monocyclic heteroaryl, and each of phenyl and monocyclic heteroaryl is optionally substituted with one or more occurrences of C ₁ -C ₆ haloalkyl. be done. In some embodiments, R ³ is:

In some embodiments, the compound is 4-(2-anilinopyrimidin-4-yl)-6-(2-chlorophenyl)-1 H-pyridin-2-one; 4-yl)-6-(3-pyridyl)-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-(4-pyridyl)-1 H-pyridin-2 -one; 4-(2-anilinopyrimidin-4-yl)-6-morpholino-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4 -pyridyl]-6-[2-(trifluoromethyl)-1-piperidyl]-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl]-1 fluoromethyl)-1-piperidyl]-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[3-(trifluoro methyl)morpholin-4-yl]-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1 H-Pyridin-2-one; 6-[4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidine- 4-yl)amino]-4-pyridyl]-1 H-pyridin-2-one; 6-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[( 2-Methylpyrimidin-4-yl)amino]-4-pyridyl]-1 H-pyridin-2-one; 4-[2-(oxazol-2-ylamino)-4-pyridyl]-6-[3-( 4-[2-[(2-methylthiazol-4-yl)amino]-4-pyridyl]-6-[3-( 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-( trifluoromethyl)-phenyl]-1 H-pyridin-2-one; 4-[2-[(2-methylpyrazol-3-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl ) phenyl]-1 H-pyridin-2-one; 4-[2-[(2-methylthiazol-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]- 1 H-pyridin-2-one; 6-(4-methyl-3-pyridyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1 H-pyridine- 2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-3-pyridyl]-1 H-pyridine-2 -one; 6-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino4-pyridyl]-1 H-pyridine -2-one; 4-[2-[(1-methylimidazol-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenylpyridin-2-one; 6-(2 -chlorophenyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1 H-pyridin-2-one; 1-methyl-2'-((2-methylpyrimidin-4-yl) -4-yl)amino)-6-(2-(trifluoromethyl)phenyl)-[4,4'-bipyridin]-2(1H)-one, and its pharmaceutically acceptable salts and stereoisomers , and tautomers.

In some embodiments, the compound is 4-(2-anilinopyrimidin-4-yl)-6-(2-chlorophenyl)-1 H-pyridin-2-one; 4-yl)-6-(3-pyridyl)-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-(4-pyridyl)-1 H-pyridin-2 -one; 4-(2-anilinopyrimidin-4-yl)-6-morpholino-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4 -pyridyl]-6-[2-(trifluoromethyl)-1-piperidyl]-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl]-1 fluoromethyl)-1-piperidyl]-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[3-(trifluoro methyl)morpholin-4-yl]-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1 H-Pyridin-2-one; 6-[4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidine- 4-yl)amino]-4-pyridyl]-1 H-pyridin-2-one; 6-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[( 2-Methylpyrimidin-4-yl)amino]-4-pyridyl]-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]- 6-[2-(trifluoromethyl)-phenyl]-1 H-pyridin-2-one; 6-(4-methyl-3-pyridyl)-4-[2-[(2-methylpyrimidin-4-yl) ) amino]-4-pyridyl]-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoro methyl)-3-pyridyl]-1 H-pyridin-2-one; 6-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-4-[2-[(2-methylpyrimidine- 4-yl)amino4-pyridyl]-1 H-pyridin-2-one; 6-(2-chlorophenyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl] -1 H-pyridin-2-one; 6-(3-cyclopropylmorpholin-4-yl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1 H -Pyridin-2-one; 1-methyl-2'-((2-methylpyrimidin-4-yl)amino)-6-(2-(trifluoromethyl)phenyl)-[4,4'-bipyridine]- 2(1H)-one, and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.

In some embodiments, the compound is 4-(2-anilinopyrimidin-4-yl)-6-(2-chlorophenyl)-1 H-pyridin-2-one; 4-yl)-6-(3-pyridyl)-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-(4-pyridyl)-1 H-pyridin-2 -one 4-(2-anilinopyrimidin-4-yl)-6-morpholino-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4- pyridyl]-6-[2-(trifluoromethyl)-1-piperidyl]-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[2-(trifluoro methyl)-1-piperidyl]-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl )morpholin-4-yl]-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1 H -pyridin-2-one; 6-[4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidine-4 -yl)amino]-4-pyridyl]-1 H-pyridin-2-one; 6-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2 -Methylpyrimidin-4-yl)amino]-4-pyridyl]-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6 -[2-(trifluoromethyl)-phenyl]-1 H-pyridin-2-one; 6-(4-methyl-3-pyridyl)-4-[2-[(2-methylpyrimidin-4-yl) amino]-4-pyridyl]-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl )-3-pyridyl]-1 H-pyridin-2-one; 6-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-4-[2-[(2-methylpyrimidine-4 -yl)amino]-4-pyridyl]-1 H-pyridin-2-one; 6-(2-chlorophenyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl ]-1 H-pyridin-2-one; 1-methyl-2'-((2-methylpyrimidin-4-yl)amino)-6-(2-(trifluoromethyl)phenyl)-[4,4' -bipyridin]-2(1H)-one, and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.

Methods of Treatment In one embodiment, a method of alleviating or treating a viral infection in a patient in need thereof, comprising:

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R ¹ is phenyl and monocyclic 5 ~6-membered heteroaryl, each of phenyl and monocyclic 5-6 membered heteroaryl being halogen, C ₁ -C ₆ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ one or more independently selected from the group consisting of -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, amino, N-C ₁ -C ₃ alkylamino and N,N- _{diC 1} -C ₃ alkylamino R ² is selected from the group consisting of H, C ₁ -C ₃ haloalkyl, and C ₁ -C 3 alkyl; R ³ is A, phenyl, and monocyclic heteroaryl; each phenyl and heteroaryl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of R ⁴ , R ⁵ , R ⁶ , and R ⁷ . each of R ⁴ , R ⁵ , R ⁶ , and R ⁷ is halogen, C ₁ -C ₆ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C From the group consisting of ₁ -C ₆ haloalkoxy, azetidine, amino, N-C ₁ -C ₃ alkylamino, N,N-diC ₁ -C ₃ alkylamino, NHSO ₂ R ⁸ , SO ₂ R ⁹ , and hydroxy independently selected; R ⁸ is selected from C ₁ -C ₃ haloalkyl and C ₁ -C ₃ alkyl; each R ⁹ is selected from R ¹⁰ , C ₁ -C ₆ alkyl, amino, N-C ₁ -C independently selected from the group consisting of _{C 1 -C} 3 alkylamino, N,N-diC 1 -C ₃ alkylamino, and C ₁ -C ₃ alkoxyC 1 -C ₃ alkyl, _{C 1 -C 6} alkyl and C ₁ - Each of C ₃ alkoxyC ₁ -C ₃ alkyl is optionally substituted with one occurrence of R ¹⁰ and each _of C ₁ -C ₆ alkyl and C _{1 -C 3} alkyl is halogen each R ¹⁰ is independently selected from the group consisting of phenyl, benzyl, monocyclic heteroaryl, C ₃ -C ₆ cycloalkyl, and heterocyclyl; Each of phenyl, benzyl, monocyclic heteroaryl, C ₃ -C ₆ cycloalkyl, and heterocyclyl is optionally substituted with one or more occurrences of R ¹¹ ; each R ¹¹ is halogen, C ₁ -C _3- haloalkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₃ alkyl, amino, N-C ₁ -C ₃ alkylamino, N,N-diC ₁ -C ₃ alkylamino, and C ₁ -C ₃ alkoxy independently selected from the group consisting of C ₁ -C ₃ alkyl; A is

R ¹² is H, halogen, COR ¹³ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl, C ₁ -C ₆ alkoxy, C selected from the group consisting of ₃ - _C6 cycloalkyl, _C1 - _C3 cyanoalkyl, and _C1 - _C3 haloalkyl; ^R13 is _C1 - _C3 alkoxy, N- _C1 - _C3 alkylamino, selected from the group consisting of N,N-diC ₁ -C ₃ alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl; Y is CH ₂ , S, SO, SO ₂ , NR ¹⁴ , NCOR ⁹ , NCOOR ¹⁵ , NSO ₂ R ⁹ , NCOCH ₂ R ⁹ , O, and a bond; R ¹⁴ is H, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl , C ₁ -C ₃ alkyl, and C ₃ -C ₆ cycloalkyl; R ¹⁵ is selected from R ¹⁰ , C ₁ -C ₆ alkyl, and C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl; , C ₁ -C ₆ alkyl and C ₁ -C ₃ alkoxy each of C ₁ -C ₃ alkyl is optionally substituted with one occurrence of R ¹⁰ , C ₁ -C ₆ alkyl and C ₁ -C ₃ alkoxy Methods are described herein in which each C ₁ -C ₃ alkyl is optionally substituted with one or more independent occurrences of halogen; Z is selected from CH and N.

In one embodiment, a method of inhibiting viral transmission, inhibiting viral entry, inhibiting viral replication, minimizing expression of viral proteins, or inhibiting viral release, the method comprising formula I administering to a patient suffering from a virus a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; contacting the virus-infected cell with an effective amount of a salt, stereoisomer, or tautomer acceptable to the compound of formula I:

where R ¹ is selected from phenyl and monocyclic 5-6 membered heteroaryl, each of phenyl and monocyclic 5-6 membered heteroaryl is halogen, C ₁ -C ₆ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, amino, N-C ₁ -C ₃ alkylamino and N,N-diC ₁ - optionally substituted with one or more substituents independently selected from the group consisting of C ₃ alkylamino; R ² is from the group consisting of H, C ₁ -C ₃ haloalkyl, and C ₁ -C 3 alkyl R ³ is selected from the group consisting of A, phenyl, and monocyclic heteroaryl, each phenyl and heteroaryl being independently selected from the group consisting of R ⁴ , R ⁵ , R ⁶ , and R ⁷ ; each of R ⁴ , R ⁵ , R ⁶ , and R ⁷ is halogen, C ₁ -C ₆ alkyl, C ₃ -C ₄ cyclo Alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, azetidine, amino, N-C ₁ -C ₃ alkylamino, N,N-diC ₁ -C ₃ alkylamino , NHSO ₂ R ⁸ , SO ₂ R ⁹ , and hydroxy; R ⁸ is selected from C ₁ -C ₃ haloalkyl and C ₁ -C ₃ alkyl; each R ⁹ is R ¹⁰ , C ₁ -C ₆ alkyl, amino, N-C ₁ -C ₃ alkylamino, N,N-diC ₁ -C ₃ alkylamino, and C _{1 -C 3} alkoxyC ₁ -C ₃ alkyl each of C ₁ -C ₆ alkyl and C ₁ -C 3 alkoxyC 1 -C ₃ alkyl independently selected from C 1 -C ₆ alkyl and C _{1 -C 6} alkyl optionally substituted with one occurrence of R ¹⁰ Each of C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl is optionally substituted with one or more independent occurrences of halogen; each R ¹⁰ is phenyl, benzyl, monocyclic heteroaryl, C ₃ - independently selected from the group consisting of C ₆ cycloalkyl, and heterocyclyl, each of phenyl, benzyl, monocyclic heteroaryl, C ₃ -C ₆ cycloalkyl, and heterocyclyl at one or more occurrences of R ¹¹ optionally substituted; each R ¹¹ is halogen, C ₁ -C ₃ haloalkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₃ alkyl, amino, N-C ₁ -C ₃ alkylamino, N,N -diC ₁ -C ₃ alkylamino, and C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl;

R ¹² is H, halogen, COR ¹³ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl, C ₁ -C ₆ alkoxy, C selected from the group consisting of ₃ - _C6 cycloalkyl, _C1 - _C3 cyanoalkyl, and _C1 - _C3 haloalkyl; ^R13 is _C1 - _C3 alkoxy, N- _C1 - _C3 alkylamino, selected from the group consisting of N,N-diC ₁ -C ₃ alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl; Y is CH ₂ , S, SO, SO ₂ , NR ¹⁴ , NCOR ⁹ , NCOOR ¹⁵ , NSO ₂ R ⁹ , NCOCH ₂ R ⁹ , O, and a bond; R ¹⁴ is H, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl , C ₁ -C ₃ alkyl, and C ₃ -C ₆ cycloalkyl; R ¹⁵ is selected from R ¹⁰ , C ₁ -C ₆ alkyl, and C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl; , C ₁ -C ₆ alkyl and C ₁ -C ₃ alkoxy each of C ₁ -C ₃ alkyl is optionally substituted with one occurrence of R ¹⁰ , C ₁ -C ₆ alkyl and C ₁ -C ₃ alkoxy Methods are described herein in which each C ₁ -C ₃ alkyl is optionally substituted with one or more independent occurrences of halogen; Z is selected from CH and N.

In some embodiments, R ¹ is a monocyclic 5-6 membered heteroaryl. In some embodiments, R ² is selected from H and C ₁ -C ₃ alkyl. In some embodiments, R ³ is selected from phenyl and monocyclic heteroaryl, and each of phenyl and monocyclic heteroaryl is optionally substituted with one or more occurrences of C ₁ -C ₆ haloalkyl. be done. In some embodiments, R ³ is:

In some embodiments, the compound is 4-(2-anilinopyrimidin-4-yl)-6-(2-chlorophenyl)-1 H-pyridin-2-one; 4-yl)-6-(3-pyridyl)-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-(4-pyridyl)-1 H-pyridin-2 -one; 4-(2-anilinopyrimidin-4-yl)-6-morpholino-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4 -pyridyl]-6-[2-(trifluoromethyl)-1-piperidyl]-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl]-1 fluoromethyl)-1-piperidyl]-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[3-(trifluoro methyl)morpholin-4-yl]-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1 H-Pyridin-2-one; 6-[4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidine- 4-yl)amino]-4-pyridyl]-1 H-pyridin-2-one; 6-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[( 2-Methylpyrimidin-4-yl)amino]-4-pyridyl]-1 H-pyridin-2-one; 4-[2-(oxazol-2-ylamino)-4-pyridyl]-6-[3-( 4-[2-[(2-methylthiazol-4-yl)amino]-4-pyridyl]-6-[3-( 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-( trifluoromethyl)-phenyl]-1 H-pyridin-2-one; 4-[2-[(2-methylpyrazol-3-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl ) phenyl]-1 H-pyridin-2-one; 4-[2-[(2-methylthiazol-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]- 1 H-pyridin-2-one; 6-(4-methyl-3-pyridyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1 H-pyridine- 2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-3-pyridyl]-1 H-pyridine-2 -one; 6-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino4-pyridyl]-1 H-pyridine -2-one; 4-[2-[(1-methylimidazol-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenylpyridin-2-one; 6-(2 -chlorophenyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1 H-pyridin-2-one; 1-methyl-2'-((2-methylpyrimidin-4-yl) -4-yl)amino)-6-(2-(trifluoromethyl)phenyl)-[4,4'-bipyridin]-2(1H)-one, and its pharmaceutically acceptable salts and stereoisomers , and tautomers.

In some embodiments, the compound is 4-(2-anilinopyrimidin-4-yl)-6-(2-chlorophenyl)-1 H-pyridin-2-one; 4-yl)-6-(3-pyridyl)-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-(4-pyridyl)-1 H-pyridin-2 -one; 4-(2-anilinopyrimidin-4-yl)-6-morpholino-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4 -pyridyl]-6-[2-(trifluoromethyl)-1-piperidyl]-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl]-1 fluoromethyl)-1-piperidyl]-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[3-(trifluoro methyl)morpholin-4-yl]-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1 H-Pyridin-2-one; 6-[4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidine- 4-yl)amino]-4-pyridyl]-1 H-pyridin-2-one; 6-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[( 2-Methylpyrimidin-4-yl)amino]-4-pyridyl]-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]- 6-[2-(trifluoromethyl)-phenyl]-1 H-pyridin-2-one; 6-(4-methyl-3-pyridyl)-4-[2-[(2-methylpyrimidin-4-yl) ) amino]-4-pyridyl]-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoro methyl)-3-pyridyl]-1 H-pyridin-2-one; 6-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-4-[2-[(2-methylpyrimidine- 4-yl)amino4-pyridyl]-1 H-pyridin-2-one; 6-(2-chlorophenyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl] -1 H-pyridin-2-one; 6-(3-cyclopropylmorpholin-4-yl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1 H -Pyridin-2-one; 1-methyl-2'-((2-methylpyrimidin-4-yl)amino)-6-(2-(trifluoromethyl)phenyl)-[4,4'-bipyridine]- 2(1H)-one, and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.

In some embodiments, the compound is 4-(2-anilinopyrimidin-4-yl)-6-(2-chlorophenyl)-1 H-pyridin-2-one; 4-yl)-6-(3-pyridyl)-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-(4-pyridyl)-1 H-pyridin-2 -one 4-(2-anilinopyrimidin-4-yl)-6-morpholino-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4- pyridyl]-6-[2-(trifluoromethyl)-1-piperidyl]-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[2-(trifluoro methyl)-1-piperidyl]-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl )morpholin-4-yl]-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1 H -pyridin-2-one; 6-[4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidine-4 -yl)amino]-4-pyridyl]-1 H-pyridin-2-one; 6-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2 -Methylpyrimidin-4-yl)amino]-4-pyridyl]-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6 -[2-(trifluoromethyl)-phenyl]-1 H-pyridin-2-one; 6-(4-methyl-3-pyridyl)-4-[2-[(2-methylpyrimidin-4-yl) amino]-4-pyridyl]-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl )-3-pyridyl]-1 H-pyridin-2-one; 6-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-4-[2-[(2-methylpyrimidine-4 -yl)amino]-4-pyridyl]-1 H-pyridin-2-one; 6-(2-chlorophenyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl ]-1 H-pyridin-2-one; 1-methyl-2'-((2-methylpyrimidin-4-yl)amino)-6-(2-(trifluoromethyl)phenyl)-[4,4' -bipyridin]-2(1H)-one, and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.

In some embodiments, the viral infection is caused by a coronavirus. In some embodiments, the viral infection is caused by a virus selected from the group consisting of coronaviruses, rhinoviruses, and flaviviruses. In some embodiments, the viral infection is caused by a rhinovirus. In some embodiments, the viral infection is caused by a flavivirus.

In some embodiments, the viral infection is 229E alphacoronavirus, NL63 alphacoronavirus, OC43 betacoronavirus, HKU1 betacoronavirus, Middle East Respiratory Syndrome (MERS) coronavirus (MERS-CoV), severe acute respiratory syndrome (SARS) caused by a coronavirus selected from the group consisting of coronavirus (SARS-CoV), and SARS-CoV-2.

In some embodiments, the viral infection is caused by SARS.

In some embodiments, the viral infection is caused by SARS-CoV.

In some embodiments, the viral infection is caused by SARS-CoV-2.

In some embodiments, the viral infection is caused by MERS-CoV.

In some embodiments, the viral infection is COVID-19.

In some embodiments, the viral infection is caused by a positive RNA virus.

In some embodiments, the virus is a positive sense RNA virus. In some embodiments, the virus is a sense RNA virus. In some embodiments, the virus is a sense strand RNA virus. In some embodiments, the virus is a positive strand RNA virus. In some embodiments, the virus is a positive (+) RNA virus. In some embodiments, the virus is a positive sense single stranded RNA virus.

In some embodiments, the positive RNA virus is selected from the group consisting of a Coronaviridae virus, a Flaviviridae virus, and a Picornaviridae virus.

In some embodiments, the positive RNA virus is selected from the group consisting of rhinoviruses, flaviviruses, picornaviruses, and coronaviruses.

In some embodiments, the positive RNA virus is a picornavirus. In some embodiments, the positive RNA virus is a rhinovirus. In some embodiments, the positive RNA virus is a human rhinovirus. In some embodiments, the positive RNA virus is a flavivirus. In some embodiments, the positive RNA virus is a coronavirus.

In some embodiments, the positive RNA virus is selected from the group consisting of SARS CoV-1, SARS CoV-2, MERS, hepatitis C (HCV), rhinovirus, dengue virus, Zika virus, and West Nile virus. .

In some embodiments, the positive RNA virus is a coronavirus.

In some embodiments, the coronavirus is selected from the group consisting of SARS CoV-1, SARS CoV-2, and MERS.

In some embodiments, the coronavirus is SARS CoV-1.

In some embodiments, the coronavirus is SARS-CoV-2.

In some embodiments, the positive RNA virus (e.g., coronavirus) is of any variant resulting from mutation or new variant emerging from another species (e.g., a mammalian species, e.g., mink).

In some embodiments, the positive RNA virus is MERS. In some embodiments, the positive RNA virus is hepatitis C. In some embodiments, the positive RNA virus is Zika virus. In some embodiments, the positive RNA virus is a dengue virus. In some embodiments, the positive RNA virus is West Nile virus.

In some embodiments, the viral infection is a respiratory viral infection.

In some embodiments, the viral infection is an upper respiratory tract viral infection or a lower respiratory tract viral infection.

In some embodiments, the method further comprises administering to the patient a therapeutically effective amount of one or more other agents or compositions.

In some embodiments, the one or more other additional agents are selected from the group consisting of ribavirin, favipiravir, ST-193, oseltamivir, zanamivir, peramivir, danoprevir, ritonavir, and remdesivir.

In some embodiments, the one or more other additional agents are protease inhibitors, fusion inhibitors, M2 proton channel blockers, polymerase inhibitors, 6-endonuclease inhibitors, neuraminidase inhibitors, reverse transcriptase inhibitors, aciclovir, acyclovir, protease inhibitors, arbidol, atazanavir, atripla, boceprevir, cidofovir, combivir, darunavir, docosanol, edoxudine, entry inhibitors, entecavir, famciclovir, fomivirsen, fosamp Lenavir, foscarnet, phosphonet, ganciclovir, ivacitabine, immunovir, idoxuridine, imiquimod, inosine, integrase inhibitors, interferon, lopinavir, loviride, moloxidine, nexavir, nucleoside analogs, penciclovir, pleconaril, podofilo toxin, ribavirin, tipranavir, trifluridine, tridivir, tromantadine, Truvada, valacyclovir, valganciclovir, vicriviroc, vidarabine, viramidine, and zodovudine.

In some embodiments, the one or more other additional agents are lamivudine, interferon alpha, VAP anti-idiotypic antibody, enfuvirtide, amantadine, rimantadine, pleconaril, aciclovir, zidovudine, fomivirsen, protease inhibitors, selected from the group consisting of double-stranded RNA activated caspase oligomerizer (DRACO), rifampicin, zanamivir, oseltamivir, danoprevir, ritonavir, and remdesivir.

In some embodiments, the one or more other additional agents include quinine (optionally in combination with clindamycin), chloroquine, amodiaquine, artemisinin and its derivatives, doxycycline, pyrimethamine, mefloquine, halofantrine, selected from the group consisting of hydroxychloroquine, eflornithine, nitazoxanide, ornidazole, paromomycin, pentamidine, primaquine, pyrimethamine, proguanil (optionally in combination with atovaquone), sulfonamides, tafenoquine, tinidazole and PPT1 inhibitors.

In some embodiments, the one or more other additional agents are RNA polymerase inhibitors.

In some embodiments, the RNA polymerase inhibitor is selected from the group consisting of remdesivir, sofosbuvir, 7-deaza-2-CMA, galidesivir, and AT-527.

In some embodiments, the RNA polymerase inhibitor is remdesivir.

In some embodiments, the one or more other additional agents are a TMPRSS protease inhibitor, a lysosome blocker (e.g., hydroxychloroquine), a PIKfyve inhibitor (e.g., apilimod), an anti-SARSCOV-2 antibody, an anti-SARSCOV -2 antibody cocktails, anti-inflammatory drugs, anti-TRIF agents (e.g., adalimumab, infliximab, etanercept, golimumab, or certolizumab), histamine H1/H2 blockers (e.g., famotidine, nizatidine, ranitidine, and cimetidine), steroids, selected from the group consisting of clotting agents, complement targeting agents, statins, and ACE inhibitors.

In some embodiments, the TMPRSS protease inhibitor is selected from the group consisting of a TMPRSS4 inhibitor, a TMPRSS11A inhibitor, a TMPRSS11D inhibitor, a TMPRSS11E1 inhibitor, and a TMPRSS2 inhibitor.

In some embodiments, the TMPRSS protease inhibitor is a TMRSS2 protease inhibitor.

In some embodiments, the TMRESS-2 protease inhibitor is selected from camostat and nafamostat.

In some embodiments, the anti-SARSCOV-2 antibody is selected from LY-CoV555 (bamlanivimab) and LY-CoV016 (etesevimab).

In some embodiments, the cocktail of anti-SARSCOV-2 antibodies is REGN-COV2.

In some embodiments, the anti-inflammatory agent is an IL-6 antagonist (eg, siltuximab, sarilumab, orokizumab, BMS-945429, circumab, and clazakizumab).

In some embodiments, the steroid is dexamethasone.

In some embodiments, the anticoagulant is low molecular weight heparin.

In some embodiments, the complement targeting agent is eculizumab.

In some embodiments, the statin is selected from the group consisting of atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

In some embodiments, the ACE inhibitor is selected from the group consisting of benazepril, captopril enalapril/enalaprilat, fosinopril, lisinopril moexipril, perindopril quinapril, and ramipril.

In some embodiments, the one or more other additional agents are remdesivir, camostat, nafamostat, hydroxychloroquine, chloroquine, apilimod, LY-CoV555 (bamlanivimab), LY-CoV016 (etesevimab), REGN-COV2, Tocilizumab, siltuximab, sarilumab, olokizumab, BMS-945429, circumab, clazakizumab, adalimumab, infliximab, etanercept, golimumab, certolizumab, famotidine, nizatidine, ranitidine, cimetidine, dexamethasone, low molecular weight heparin, eculizumab, atorvastatin, fluvastatin, lovastatin, pitavasta Chin , pravastatin, rosuvastatin, simvastatin, benazepril, captopril, enalapril/enalaprilat, fosinopril, lisinopril, moexipril, perindopril, quinapril, and ramipril.

In some embodiments, the method includes remdesivir, sofosbuvir, 7-deaza-2-CMA, galidesivir, AT-527, temoporfin, novobiocin, curcumin, voxilaprevir, grazoprevir, glecaprevir, camostat, nafamostat, hydroxychloroquine, chloroquine, Apilimod, imatinib, dasatinib, ponatinib, velpatasvir, ledipasvir, elbasvir, pibrentasvir, NITD008, LY-CoV555 (bamlanivimab), LY-CoV016 (etesevimab), REGN-COV2, tocilizumab, siltuximab, sarilumab, olokizumab, BMS-945 429, Silkumab, Clazakizumab, adalimumab, infliximab, etanercept, golimumab, certolizumab, famotidine, nizatidine, ranitidine, cimetidine, dexamethasone, low molecular weight heparin, eculizumab, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, benazepril, captopril enalapril/enala Prilato, administering one or more other additional agents selected from the group consisting of fosinopril, lisinopril moexipril, perindopril quinapril, ramipril, and adoptive NK cell therapy.

In some embodiments, the one or more other additional agents are selected from the group consisting of ABL inhibitors and JAK inhibitors.

In some embodiments, the one or more other additional agents are ABL inhibitors (eg, imatinib, dasatinib, or ponatinib). In some embodiments, the ABL inhibitor is selected from the group consisting of imatinib, dasatinib, and ponatinib. In some embodiments, the ABL inhibitor is imatinib. In some embodiments, the ABL inhibitor is dasatinib. In some embodiments, the ABL inhibitor is ponatinib.

In some embodiments, the one or more other additional agents are JAK inhibitors. In some embodiments, the JAK inhibitor is selected from the group consisting of baricitinib, ruxolitinib, tofacitinib, and upadacitinib. In some embodiments, the JAK inhibitor is baricitinib. In some embodiments, the JAK inhibitor is ruxolitinib. In some embodiments, the JAK inhibitor is tofacitinib. In some embodiments, the JAK inhibitor is upadacitinib.

In some embodiments, the one or more other additional agents are protease inhibitors. In embodiments, the protease inhibitor is selected from the group consisting of temoporfin, novobiocin, curcumin, voxilaprevir, grazoprevir, and glecaprevir.

In some embodiments, the one or more other additional agents are NS5A inhibitors. In embodiments, the NS5A inhibitor is selected from the group consisting of velpatasvir, ledipasvir, elbasvir, and pibrentasvir.

In some embodiments, the one or more other additional agents are pyrimidine synthesis inhibitors. In some embodiments, the pyrimidine synthesis inhibitor is NITD008.

In some embodiments, the one or more other additional agents are adoptive natural killer (NK) cell therapy.

In some embodiments, the additional therapeutic agent is a vaccine.

In some embodiments, the vaccine is a coronavirus vaccine.

In some embodiments, the vaccine comprises BNT162b2, mRNA-1273, AZD1222, and Ad26. COV2. selected from the group consisting of S.

In some embodiments, the vaccine is a protein-based vaccine.

In some embodiments, the vaccine is an RNA-based vaccine.

In some embodiments, the vaccine is an attenuated viral vaccine.

In some embodiments, the vaccine is an inactivated virus vaccine.

In some embodiments, the vaccine is a non-replicating viral vector vaccine.

In some embodiments, the compound is administered orally to the patient.

In some embodiments, the compound is administered parenterally to the patient.

In one embodiment, a method of treating a Coronaviridae infection in a patient in need thereof, comprising:

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R ¹ is phenyl and monocyclic 5 ~6-membered heteroaryl, each of phenyl and monocyclic 5-6 membered heteroaryl being halogen, C ₁ -C ₆ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ one or more independently selected from the group consisting of -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, amino, N-C ₁ -C ₃ alkylamino and N,N- _{diC 1} -C ₃ alkylamino R ² is selected from the group consisting of H, C ₁ -C ₃ haloalkyl, and C ₁ -C 3 alkyl; R ³ is selected from A, phenyl, and monocyclic heteroaryl; each phenyl and heteroaryl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of R ⁴ , R ⁵ , R ⁶ , and R ⁷ . ; R ⁴ , R ⁵ , R ⁶ , and R ⁷ each represent halogen, C ₁ -C ₆ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ Independent from the group consisting of -C ₆ haloalkoxy, azetidine, amino, N-C ₁ -C ₃ alkylamino, N,N-diC ₁ -C ₃ alkylamino, NHSO ₂ R ⁸ , SO ₂ R ⁹ , and hydroxy R ⁸ is selected from C ₁ -C ₃ haloalkyl and C ₁ -C ₃ alkyl; each R ⁹ is selected from R ¹⁰ , C ₁ -C ₆ alkyl, amino, N-C ₁ -C ₃ independently selected from the group _consisting of alkylamino, N,N-diC ₁ -C ₃ alkylamino, and C ₁ -C _{3 alkoxyC 1 -C 3} alkyl, C _{1 -C 6} alkyl and C ₁ -C Each of ₃ -alkoxy C ₁ -C ₃ alkyl is optionally substituted with one occurrence of R ¹⁰ and each of C ₁ -C ₆ alkyl and C ₁ -C ₃ alkyl and C ₁ -C ₃ alkyl is substituted with one of the halogens. optionally substituted in one or more independent occurrences; each R ¹⁰ is independently selected from the group consisting of phenyl, benzyl, monocyclic heteroaryl, C ₃ -C ₆ cycloalkyl, and heterocyclyl, phenyl , benzyl, monocyclic heteroaryl, C ₃ -C ₆ cycloalkyl, and heterocyclyl are each optionally substituted with one or more occurrences of R ¹¹ ; each R ¹¹ is halogen, C ₁ -C ₃ Haloalkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₃ alkyl, amino, N-C ₁ -C ₃ alkylamino, N,N-diC ₁ -C ₃ alkylamino, and C ₁ -C ₃ alkoxyC independently selected from the group consisting of ₁ -C ₃ alkyl; A is

R ¹² is H, halogen, COR ¹³ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl, C ₁ -C ₆ alkoxy, C selected from the group consisting of ₃ - _C6 cycloalkyl, _C1 - _C3 cyanoalkyl, and _C1 - _C3 haloalkyl; ^R13 is _C1 - _C3 alkoxy, N- _C1 - _C3 alkylamino, selected from the group consisting of N,N-diC ₁ -C ₃ alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl; Y is CH ₂ , S, SO, SO ₂ , NR ¹⁴ , NCOR ⁹ , NCOOR ¹⁵ , NSO ₂ R ⁹ , NCOCH ₂ R ⁹ , O, and a bond; R ¹⁴ is H, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl , C ₁ -C ₃ alkyl, and C ₃ -C ₆ cycloalkyl; R ¹⁵ is selected from R ¹⁰ , C ₁ -C ₆ alkyl, and C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl; , C ₁ -C ₆ alkyl and C ₁ -C ₃ alkoxy each of C ₁ -C ₃ alkyl is optionally substituted with one occurrence of R ¹⁰ , C ₁ -C ₆ alkyl and C ₁ -C ₃ alkoxy Methods are described herein in which each C ₁ -C ₃ alkyl is optionally substituted with one or more independent occurrences of halogen; Z is selected from CH and N.

In some embodiments, R ¹ is a monocyclic 5-6 membered heteroaryl. In some embodiments, R ² is selected from H and C ₁ -C ₃ alkyl. In some embodiments, R ³ is selected from phenyl and monocyclic heteroaryl, and each of phenyl and monocyclic heteroaryl is optionally substituted with one or more occurrences of C ₁ -C ₆ haloalkyl. be done. In some embodiments, R ³ is:

In some embodiments, the compound is 4-(2-anilinopyrimidin-4-yl)-6-(2-chlorophenyl)-1 H-pyridin-2-one; 4-yl)-6-(3-pyridyl)-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-(4-pyridyl)-1 H-pyridin-2 -one; 4-(2-anilinopyrimidin-4-yl)-6-morpholino-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4 -pyridyl]-6-[2-(trifluoromethyl)-1-piperidyl]-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl]-1 fluoromethyl)-1-piperidyl]-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[3-(trifluoro methyl)morpholin-4-yl]-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1 H-Pyridin-2-one; 6-[4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidine- 4-yl)amino]-4-pyridyl]-1 H-pyridin-2-one; 6-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[( 2-Methylpyrimidin-4-yl)amino]-4-pyridyl]-1 H-pyridin-2-one; 4-[2-(oxazol-2-ylamino)-4-pyridyl]-6-[3-( 4-[2-[(2-methylthiazol-4-yl)amino]-4-pyridyl]-6-[3-( 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-( trifluoromethyl)-phenyl]-1 H-pyridin-2-one; 4-[2-[(2-methylpyrazol-3-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl ) phenyl]-1 H-pyridin-2-one; 4-[2-[(2-methylthiazol-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]- 1 H-pyridin-2-one; 6-(4-methyl-3-pyridyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1 H-pyridine- 2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-3-pyridyl]-1 H-pyridine-2 -one; 6-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino4-pyridyl]-1 H-pyridine -2-one; 4-[2-[(1-methylimidazol-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenylpyridin-2-one; 6-(2 -chlorophenyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1 H-pyridin-2-one; 1-methyl-2'-((2-methylpyrimidin-4-yl) -4-yl)amino)-6-(2-(trifluoromethyl)phenyl)-[4,4'-bipyridin]-2(1H)-one, and its pharmaceutically acceptable salts and stereoisomers , and tautomers.

In some embodiments, the compound is 4-(2-anilinopyrimidin-4-yl)-6-(2-chlorophenyl)-1 H-pyridin-2-one; 4-yl)-6-(3-pyridyl)-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-(4-pyridyl)-1 H-pyridin-2 -one; 4-(2-anilinopyrimidin-4-yl)-6-morpholino-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4 -pyridyl]-6-[2-(trifluoromethyl)-1-piperidyl]-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl]-1 fluoromethyl)-1-piperidyl]-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[3-(trifluoro methyl)morpholin-4-yl]-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1 H-Pyridin-2-one; 6-[4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidine- 4-yl)amino]-4-pyridyl]-1 H-pyridin-2-one; 6-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[( 2-Methylpyrimidin-4-yl)amino]-4-pyridyl]-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]- 6-[2-(trifluoromethyl)-phenyl]-1 H-pyridin-2-one; 6-(4-methyl-3-pyridyl)-4-[2-[(2-methylpyrimidin-4-yl) ) amino]-4-pyridyl]-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoro methyl)-3-pyridyl]-1 H-pyridin-2-one; 6-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-4-[2-[(2-methylpyrimidine- 4-yl)amino4-pyridyl]-1 H-pyridin-2-one; 6-(2-chlorophenyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl] -1 H-pyridin-2-one; 6-(3-cyclopropylmorpholin-4-yl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1 H -Pyridin-2-one; 1-methyl-2'-((2-methylpyrimidin-4-yl)amino)-6-(2-(trifluoromethyl)phenyl)-[4,4'-bipyridine]- 2(1H)-one, and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.

In some embodiments, the compound is 4-(2-anilinopyrimidin-4-yl)-6-(2-chlorophenyl)-1 H-pyridin-2-one; 4-yl)-6-(3-pyridyl)-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-(4-pyridyl)-1 H-pyridin-2 -one 4-(2-anilinopyrimidin-4-yl)-6-morpholino-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4- pyridyl]-6-[2-(trifluoromethyl)-1-piperidyl]-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[2-(trifluoro methyl)-1-piperidyl]-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl )morpholin-4-yl]-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1 H -pyridin-2-one; 6-[4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidine-4 -yl)amino]-4-pyridyl]-1 H-pyridin-2-one; 6-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2 -Methylpyrimidin-4-yl)amino]-4-pyridyl]-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6 -[2-(trifluoromethyl)-phenyl]-1 H-pyridin-2-one; 6-(4-methyl-3-pyridyl)-4-[2-[(2-methylpyrimidin-4-yl) amino]-4-pyridyl]-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl )-3-pyridyl]-1 H-pyridin-2-one; 6-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-4-[2-[(2-methylpyrimidine-4 -yl)amino]-4-pyridyl]-1 H-pyridin-2-one; 6-(2-chlorophenyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl ]-1 H-pyridin-2-one; 1-methyl-2'-((2-methylpyrimidin-4-yl)amino)-6-(2-(trifluoromethyl)phenyl)-[4,4' -bipyridin]-2(1H)-one, and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.

In some embodiments, the Coronaviridae infection is caused by SARS-CoV-2.

In some embodiments, the coronavirus infection is COVID-19.

In some embodiments, the Coronaviridae infection is caused by a coronavirus.

In some embodiments, the coronavirus is 229E alphacoronavirus, NL63 alphacoronavirus, OC43 betacoronavirus, HKU1 betacoronavirus, Middle East Respiratory Syndrome (MERS) coronavirus (MERS-CoV), severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), and SARS-CoV-2.

In some embodiments, the coronavirus is SARS-CoV-2.

In some embodiments, the method further comprises administering to the patient a therapeutically effective amount of one or more other agents or compositions.

In some embodiments, the one or more other additional agents are selected from the group consisting of ribavirin, favipiravir, ST-193, oseltamivir, zanamivir, peramivir, danoprevir, ritonavir, and remdesivir.

In some embodiments, the one or more other additional agents are protease inhibitors, fusion inhibitors, M2 proton channel blockers, polymerase inhibitors, 6-endonuclease inhibitors, neuraminidase inhibitors, reverse transcriptase inhibitors, aciclovir, acyclovir, protease inhibitors, arbidol, atazanavir, atripla, boceprevir, cidofovir, combivir, darunavir, docosanol, edoxudine, entry inhibitors, entecavir, famciclovir, fomivirsen, fosamp Lenavir, foscarnet, phosphonet, ganciclovir, ivacitabine, immunovir, idoxuridine, imiquimod, inosine, integrase inhibitors, interferon, lopinavir, loviride, moloxidine, nexavir, nucleoside analogs, penciclovir, pleconaril, podofilo toxin, ribavirin, tipranavir, trifluridine, tridivir, tromantadine, Truvada, valacyclovir, valganciclovir, vicriviroc, vidarabine, viramidine, and zodovudine.

In some embodiments, the one or more other additional agents are lamivudine, interferon alpha, VAP anti-idiotypic antibody, enfuvirtide, amantadine, rimantadine, pleconaril, aciclovir, zidovudine, fomivirsen, protease inhibitors, selected from the group consisting of double-stranded RNA activated caspase oligomerizer (DRACO), rifampicin, zanamivir, oseltamivir, danoprevir, ritonavir, and remdesivir.

In some embodiments, the one or more other additional agents include quinine (optionally in combination with clindamycin), chloroquine, amodiaquine, artemisinin and its derivatives, doxycycline, pyrimethamine, mefloquine, halofantrine, selected from the group consisting of hydroxychloroquine, eflornithine, nitazoxanide, ornidazole, paromomycin, pentamidine, primaquine, pyrimethamine, proguanil (optionally in combination with atovaquone), sulfonamides, tafenoquine, tinidazole and PPT1 inhibitors.

In some embodiments, the one or more other additional agents are RNA polymerase inhibitors.

In some embodiments, the RNA polymerase inhibitor is selected from the group consisting of remdesivir, sofosbuvir, 7-deaza-2-CMA, galidesivir, and AT-527.

In some embodiments, the RNA polymerase inhibitor is remdesivir.

In some embodiments, the one or more other additional agents are a TMPRSS protease inhibitor, a lysosome blocker (e.g., hydroxychloroquine), a PIKfyve inhibitor (e.g., apilimod), an anti-SARSCOV-2 antibody, an anti-SARSCOV -2 antibody cocktails, anti-inflammatory drugs, anti-TRIF agents (e.g., adalimumab, infliximab, etanercept, golimumab, or certolizumab), histamine H1/H2 blockers (e.g., famotidine, nizatidine, ranitidine, and cimetidine), steroids, selected from the group consisting of clotting agents, complement targeting agents, statins, and ACE inhibitors.

In some embodiments, the TMPRSS protease inhibitor is selected from the group consisting of a TMPRSS4 inhibitor, a TMPRSS11A inhibitor, a TMPRSS11D inhibitor, a TMPRSS11E1 inhibitor, and a TMPRSS2 inhibitor.

In some embodiments, the TMPRSS protease inhibitor is a TMRSS2 protease inhibitor.

In some embodiments, the TMRESS-2 protease inhibitor is selected from camostat and nafamostat.

In some embodiments, the anti-SARS CoV-2 antibody is selected from LY-CoV555 (bamlanivimab) and LY-CoV016 (etesevimab).

In some embodiments, the cocktail of anti-SARS CoV-2 antibodies is REGN-COV2.

In some embodiments, the anti-inflammatory agent is an IL-6 antagonist (eg, siltuximab, sarilumab, orokizumab, BMS-945429, circumab, and clazakizumab).

In some embodiments, the steroid is dexamethasone.

In some embodiments, the anticoagulant is low molecular weight heparin.

In some embodiments, the complement targeting agent is eculizumab.

In some embodiments, the statin is selected from the group consisting of atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

In some embodiments, the ACE inhibitor is selected from the group consisting of benazepril, captopril enalapril/enalaprilat, fosinopril, lisinopril moexipril, perindopril quinapril, and ramipril.

In some embodiments, the one or more other additional agents are remdesivir, camostat, nafamostat, hydroxychloroquine, chloroquine, apilimod, LY-CoV555 (bamlanivimab), LY-CoV016 (etesevimab), REGN-COV2, Tocilizumab, siltuximab, sarilumab, olokizumab, BMS-945429, sirukumab, clazakizumab, adalimumab, infliximab, etanercept, golimumab, certolizumab, famotidine, nizatidine, ranitidine, cimetidine, dexamethasone, low molecular weight heparin, eculizumab, atorvastatin, fluvastatin, lovastatin, pitavastatin , pravastatin, rosuvastatin, simvastatin, benazepril, captopril, enalapril/enalaprilat, fosinopril, lisinopril, moexipril, perindopril, quinapril, and ramipril.

In some embodiments, the method includes remdesivir, sofosbuvir, 7-deaza-2-CMA, galidesivir, AT-527, temoporfin, novobiocin, curcumin, voxilaprevir, grazoprevir, glecaprevir, camostat, nafamostat, hydroxychloroquine, chloroquine, Apilimod, imatinib, dasatinib, ponatinib, velpatasvir, ledipasvir, elbasvir, pibrentasvir, NITD008, LY-CoV555 (bamlanivimab), LY-CoV016 (etesevimab), REGN-COV2, tocilizumab, siltuximab, sarilumab, olokizumab, BMS-9454 29, Silkumab, Clazakizumab, adalimumab, infliximab, etanercept, golimumab, certolizumab, famotidine, nizatidine, ranitidine, cimetidine, dexamethasone, low molecular weight heparin, eculizumab, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, benazepril, captopril enalapril/enala Prilato, administering one or more other additional agents selected from the group consisting of fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and adoptive NK cell therapy.

In some embodiments, the one or more other additional agents are ABL inhibitors (eg, imatinib, dasatinib, or ponatinib).

In some embodiments, the one or more other additional agents are protease inhibitors. In embodiments, the protease inhibitor is selected from the group consisting of temoporfin, novobiocin, curcumin, voxilaprevir, grazoprevir, and glecaprevir.

In some embodiments, the one or more other additional agents are NS5A inhibitors. In embodiments, the NS5A inhibitor is selected from the group consisting of velpatasvir, ledipasvir, elbasvir, and pibrentasvir.

In some embodiments, the one or more other additional agents are pyrimidine synthesis inhibitors. In some embodiments, the pyrimidine synthesis inhibitor is NITD008.

In some embodiments, the one or more other additional agents are adoptive natural killer (NK) cell therapy.

In some embodiments, the additional therapeutic agent is a vaccine.

In some embodiments, the vaccine is a coronavirus vaccine.

In some embodiments, the vaccine comprises BNT162b2, mRNA-1273, AZD1222, and Ad26. COV2. selected from the group consisting of S.

In some embodiments, the vaccine is a protein-based vaccine.

In some embodiments, the vaccine is an RNA-based vaccine.

In some embodiments, the vaccine is an attenuated viral vaccine.

In some embodiments, the vaccine is an inactivated virus vaccine.

In some embodiments, the vaccine is a non-replicating viral vector vaccine.

In some embodiments, the compound is administered orally to the patient.

In some embodiments, the compound is administered parenterally to the patient.

In some embodiments, the Coronaviridae infections described herein are caused by coronaviruses. In some embodiments, the Coronaviridae infection described herein is caused by SARS-CoV-2. In some embodiments, the coronavirus infection described herein is COVID-19. In some embodiments, the coronavirus is 229E alphacoronavirus, NL63 alphacoronavirus, OC43 betacoronavirus, HKU1 betacoronavirus, Middle East Respiratory Syndrome (MERS) coronavirus (MERS-CoV), severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV). In some embodiments, the coronavirus is SARS-CoV-2.

In some embodiments, the methods described herein prevent morbidity or mortality in a patient. In some embodiments, the methods described herein minimize or prevent the need to hospitalize the patient or minimize or prevent the need to connect the patient to a ventilator. In some embodiments, the methods described herein minimize or prevent the need to admit the patient to an intensive care unit. In some embodiments, the methods described herein minimize or prevent the need to connect a patient to a ventilator.

Methods for determining antiviral activity of SARS CoV-1, SARS CoV-2, MERS, hepatitis C, dengue virus, or Zika virus are known to those skilled in the art and include cytopathic effect assay (CPE), RT/PCR assay. , replicon assays with reporter readouts, or viral plaque assays.

Methods for determining inhibition of autophagosome formation in virus-infected cells are known to those skilled in the art and include speck determination by Cyto-ID® or electron microscopy, LC3-luciferase fusion assay or LC3-GFP/mCherry flux assay. Includes an autophagy flux assay or determination of the LC3-I/LC3-II ratio. Such autophagy assays can also be used to assess activation of autophagy by nonstructural protein 6 (nsp6) or related +RNA virus-encoded proteins.

Combination Therapy A compound described herein, e.g., a compound of formula I as defined herein, may be used to treat a disorder described herein, e.g., an infection by a virus described herein, such as a coronavirus. It can be administered in combination with one or more additional therapeutic agents (eg, one or more other additional agents described herein) in order to do so. For example, a pharmaceutical composition comprising a compound described herein, e.g., a compound of Formula I as defined herein, one or more additional therapeutic agents, and a pharmaceutically acceptable excipient, provided in this disclosure. In some embodiments, a compound of Formula I as defined herein and one additional therapeutic agent are administered. In some embodiments, a compound of Formula I as defined herein and two additional therapeutic agents are administered. In some embodiments, a compound of Formula I as defined herein and three additional therapeutic agents are administered. Combination therapy can be accomplished by administering two or more therapeutic agents, each of which is formulated and administered separately. For example, a compound of Formula I as defined herein and the additional therapeutic agent can be formulated and administered separately. Combination therapy involves the use of two or more therapeutic agents in a single formulation, e.g., a compound of formula I as one therapeutic agent and one such as an antibiotic, viral protease inhibitor, or antiviral nucleoside antimetabolite. This can also be achieved by administering a pharmaceutical composition containing the above additional therapeutic agents. For example, a compound of Formula I as defined herein and the additional therapeutic agent can be administered in a single formulation. Other combinations are also included in combination therapy. Two or more agents in combination therapy can be administered at the same time, but this is not required. For example, administration of a first agent (or combination of agents) can precede administration of a second agent (or combination of agents) by minutes, hours, days, or weeks. Thus, two or more agents may be administered within minutes of each other, or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other, or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other. administered within 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days, or within or within 2, 3, 4, 5, 6, 7, 8, 9 weeks of each other. Can be administered within more than a week. In some cases even longer intervals are possible. In many cases, it is desirable, but not necessary, for two or more drugs used in combination therapy to be present in the patient's body at the same time.

Combination therapy can also include two or more administrations of one or more agents used in combination with the component agents in different orders. For example, when drug X and drug Y are used in combination, they can be administered in any combination one or more times, for example, X-Y-X, X-X-Y, Y- The order is XY, YYX, XXYY, etc.

Pharmaceutical Compositions and Kits Another aspect of the present disclosure provides pharmaceutical compositions comprising a compound disclosed herein formulated with a pharmaceutically acceptable carrier. In particular, the present disclosure provides pharmaceutical compositions comprising a compound disclosed herein formulated with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, or aerosol administration, but do not require any The most appropriate form of administration in any particular case will depend on the extent and severity of the condition being treated and the nature of the particular compound used. For example, the disclosed compositions may be formulated as unit doses and/or for oral or subcutaneous administration.

Exemplary pharmaceutical compositions include the form of a pharmaceutical preparation, e.g., one or more of the compounds described herein as an active ingredient, in an organic or inorganic carrier suitable for topical, enteral or parenteral application. or in solid, semi-solid, or liquid form, mixed with excipients. The active ingredient can be formulated with conventional non-toxic pharmaceutically acceptable carriers, for example, tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. may be done. The active substance compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the disease process or condition.

For preparing solid compositions such as tablets, the main active ingredient is combined with conventional pharmaceutical carriers such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums. Solid preformulation compositions containing a homogeneous mixture of a compound provided herein, or a non-toxic pharmaceutically acceptable salt thereof, in admixture with tablet components and other pharmaceutical diluents, such as water. can be formed. When these preformulation compositions are referred to as homogeneous, the active ingredient is uniformly dispersed throughout the composition such that the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. means to be

In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the subject composition may be supplemented with one or more pharmaceutically acceptable carriers, such as sodium citrate or diphosphate. calcium, etc., and/or mixed with any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as carboxylic acid. (3) Wetting agents, such as glycerol, (4) Disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, such as methylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and/or acacia. , and sodium carbonate, (5) solution retarding agents, such as paraffin, (6) absorption enhancers, such as quaternary ammonium compounds, (7) wetting agents, such as acetyl alcohol and glycerol monostearate, (8) absorbents such as kaolin and bentonite clay, (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof, and (10) colorants. For capsules, tablets, and pills, the composition may also include a buffering agent. Solid compositions of a similar type may also be employed as fillers in soft- and hard-filled gelatin capsules using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may contain binders (e.g. gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g. sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants or dispersants. can be prepared using Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms such as dragees, capsules, pills, and granules, may optionally be coated with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. May be scored or prepared.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the subject composition, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, etc. Ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil) ), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

Suspensions contain, in addition to the subject composition, suspensions such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof. It may contain a clouding agent.

Formulations for rectal or vaginal administration may be presented as suppositories, in which the subject composition is combined with one or more suitable non-containing agents, including, for example, cocoa butter, polyethylene glycols, suppository waxes, or salicylates. They can be prepared by mixing with irritating excipients or carriers, which are solid at room temperature but become liquid at body temperature, thus melting in body cavities and releasing the active agent.

Dosage forms for transdermal administration of the subject compositions include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be required.

Ointments, pastes, creams, and gels contain, in addition to the subject composition, animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide. , or mixtures thereof.

Powders and sprays can contain, in addition to the subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, and polyamide powder, or mixtures of these substances. The spray may further contain customary propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

Compositions and compounds of the present disclosure may alternatively be administered by aerosol. This is accomplished by preparing aqueous aerosols, liposome preparations, or solid particles containing the compound. Non-aqueous (eg, fluorocarbon propellant) suspensions may be used. Ultrasonic nebulizers may be used to minimize exposure of the drug to shear that can result in degradation of compounds contained in the subject composition. Typically, aqueous aerosols are made by formulating an aqueous solution or suspension of the subject composition with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary depending on the requirements of the particular target composition, but typically include nonionic surfactants (Tween, Pluronic, or polyethylene glycol), non-toxic proteins such as serum albumin, sorbitan esters, etc. , oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

Pharmaceutical compositions of the present disclosure suitable for parenteral administration can be prepared in one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions or sterilized immediately prior to use. a sterile powder that can be reconstituted into an injectable solution or dispersion, containing the subject composition in combination with antioxidants, buffers, bacteriostatic agents, solutes to render it isotonic with the blood of the intended recipient; Alternatively, a suspending agent or thickening agent may be included.

Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions provided herein include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol), and suitable mixtures thereof; Included are vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate and cyclodextrins. Proper fluidity may be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

In another aspect, enteral pharmaceutical formulations are provided that include the disclosed compounds and enteric materials and pharmaceutically acceptable carriers or excipients thereof. Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach and predominantly soluble in intestinal fluids at certain pHs. The small intestine is the part of the gastrointestinal tract (intestine) between the stomach and large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5, and the pH of the distal ileum is about 7.5.

Thus, the enteric material may be, for example, about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, about 8.0, about 8.2, about 8.4, about Does not dissolve up to a pH of 8.6, about 8.8, about 9.0, about 9.2, about 9.4, about 9.6, about 9.8, or about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, Hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methyl methacrylic acid and methyl methacrylate, methyl acrylate Copolymers of methyl methacrylate and methacrylic acid, copolymers of methyl vinyl ether and maleic anhydride (Gantrez ES series), ethyl methacrylate-methyl methacrylate-chlorotrimethylammonium ethyl acrylate copolymers, natural resins such as zein, shellac and copal colofolium (copal collophorium), and some commercially available enteric dispersions (e.g. Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateri c, and Aquateric). The solubility of each of the above materials is known or can be readily determined in vitro. While the foregoing is a list of possible materials, one skilled in the art with the benefit of this disclosure will appreciate that it is not exhaustive and that there are other enteric materials that would meet the purposes described herein. You will recognize that.

Advantageously, for use such as by a purchaser in need of treatment for a disease or disorder described herein, such as an infection caused by a pathogen, e.g. a virus, fungus, or protozoa, as described herein. Provided herein are kits for: Such kits will include a suitable dosage form, such as those described above, and instructions describing how to use such dosage form to mediate, reduce, or prevent inflammation. The instructions will instruct the purchaser or health care professional to administer the dosage form according to modes of administration known to those skilled in the art. Such kits may advantageously be packaged and sold in single or multiple kit units. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs generally consist of a sheet of relatively rigid material covered with a foil of preferably transparent plastic material. During the packaging process, depressions are formed in the plastic foil. The depression has the size and shape of the tablet or capsule to be packaged. The tablet or capsule is then placed in the depression and the sheet of relatively stiff material is sealed against the plastic foil on the side of the foil opposite the direction in which the depression was formed. As a result, the tablet or capsule is sealed in the cavity between the plastic foil and the sheet. Preferably, the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure to the recesses, thereby forming an opening in the sheet at the location of the recess. The tablet or capsule can then be removed through the opening.

It may be desirable to provide a memory aid on the kit, for example in the form of a number next to the tablet or capsule, which number indicates that the tablet or capsule so designated is to be taken. Correspond to the day of the regimen. Another example of such a memory aid is, for example, a calendar printed on a card, such as "Week 1, Monday, Tuesday, etc..." Week 2, Monday, Tuesday,... etc. Other types of memory aids will be readily apparent. A "daily dose" can be a single tablet or capsule, or multiple tablets or capsules, taken on a given day. Also, the daily dose of the first compound may consist of one tablet or capsule, and the daily dose of the second compound may consist of multiple tablets or capsules, and vice versa. Memory aids need to reflect this.

The compounds described herein can be prepared in a number of ways based on the teachings contained herein and the disclosure of synthetic procedures in the art. In the description of the synthetic method described below, all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, experimental duration and precise working procedure, are included in the reaction, unless otherwise indicated. It should be understood that this can be selected as a standard condition. Those skilled in the art of organic synthesis understand that the functionality present in various parts of the molecule should be compatible with the proposed reagents and reactions. Substitutions that are incompatible with the reaction conditions will be apparent to those skilled in the art and alternative methods are therefore indicated. Starting materials for the Examples are either commercially available or readily prepared from known materials by standard methods.

Abbreviations: MS: Mass spectrometry.

Exemplary synthesis of compounds 1, 2, 3, and 4.
Compounds 1, 2, 3, and 4 were prepared according to the synthetic procedure described in WO 2019/038389.

For compound 3: MS m/z 438.1 (M+H ⁺ ).

SARS CoV-1 CPE assay for antiviral activity.
A cell-based assay is used to measure the cytopathic effect (CPE) of the virus infecting Vero E6 host cells. Host cells infected with a virus die as a result of the virus hijacking the cellular machinery for genome replication. CPE reduction assays indirectly monitor the effectiveness of antiviral agents acting through various molecular mechanisms by measuring host cell viability 3 days after virus inoculation. Antiviral compounds are identified as those that protect host cells from the cytopathic effects of viruses, thereby increasing survival.

Vero E6 cells selected for expression of the SARS CoV receptor (ACE2; angiotensin converting enzyme 2) are used for CPE assays. Cells are grown in MEM/10% HI FBS and harvested in MEM/1% PSG/2% HI FBS. Cells were batch inoculated with coronavirus (Toronto 2 SARS CoV-1 at M.O.I. ~ 0.002, and 5% cell viability was obtained 72 hours after infection. Test compounds were predosed (1 well Assay plates (ARP; Corning 3712BC) are prepared in the BSL-2 lab by adding 5 μL assay medium to each well. The plate is transferred to a BSL-3 facility and a 25 μL aliquot of virus-inoculated cells (4000 Vero E6 cells/well) is added to each well in columns 3-22. Wells in columns 23-24 contain only virus-infected cells. (no compound treatment). Prior to virus infection, add a 25 μL aliquot of cells to columns 1-2 of each plate to serve as a cell only (no virus) control. Place plates at 37° C./5% CO ₂ . After 72 hours of incubation at 90% humidity, 30 μL of Cell Titer-Glo (Promega) is added to each well. After 10 minutes of incubation at room temperature, luminescence is read using a Perkin Elmer Envision or BMG CLARIOstar plate reader to determine cell survival. The raw data from each test well is normalized to the average signal of uninfected cells (average cells; 100% inhibition) and virus-infected cells only (average virus; 0% inhibition) using the following formula: Calculate the percent inhibition of CPE: percent inhibition = 100 * (test compound - average virus) / (average cells - average virus). The SARS CPE assay was performed under BSL-3 confinement and plated before reading the luminescence. shall be sealed with a transparent cover and the surface shall be decontaminated.

Cytotoxicity (CC50) of compounds is evaluated in a BSL-2 counterscreen as follows: host cells in culture are aliquoted (25 μl) into each well of an assay plate prepared with test compound as described above. cells/well). Cells alone (100% viability) and cells treated with Hyamine at a final concentration of 100 μM (0% viability) serve as high and low signal controls for cytotoxic effects in the assay, respectively. DMSO is maintained at a constant concentration (0.3%) for all wells as determined by the dilution factor of the stock test compound concentration. After incubating the plates for 72 hours at 37° C./5% CO ₂ and 90% humidity, 30 μl Cell Titer-Glo (Promega) is added to each well. After incubation for 10 minutes at room temperature, read luminescence and measure cell viability using a BMG PHERAstar plate reader.

SARS CoV-1 CPE assay for synergy in combination with remdesivir.
One or more other additional agents are tested in combination with remdesivir using the assay protocol of Example 2. Each drug is evaluated in a 10-point dose response (high concentration 15 μM → 2-fold dilution).

SARS CoV-1 CPE assay for synergy in combination with hydroxychloroquine.
One or more other additional agents are tested in combination with hydroxychloroquine (HCQ) using the assay protocol of Example 2. Each drug is evaluated in a 10-point dose response (high concentration 15 μM → 2-fold dilution).

SARS CoV-2 CPE assay for antiviral activity.
A cell-based assay is used to measure the cytopathic effect (CPE) of the virus infecting Vero E6 host cells. Host cells infected with a virus die as a result of the virus hijacking the cellular machinery for genome replication. CPE reduction assays indirectly monitor the effectiveness of antiviral agents acting through various molecular mechanisms by measuring host cell viability 3 days after virus inoculation. Antiviral compounds are identified as those that protect host cells from the cytopathic effects of viruses, thereby increasing survival.

Vero E6 cells selected for expression of the SARS CoV receptor (ACE2; angiotensin converting enzyme 2) are used for CPE assays. Cells are grown in MEM/10% HI FBS and harvested in MEM/1% PSG/2% HI FBS. Cells were infected with coronavirus USA_WA1/2020 SARS CoV-2 by M. O. I. Batch inoculation at ~0.002 resulted in 5% cell viability 72 hours after infection. Assay plates (ARP; Corning 3712BC) predosed with test compounds (30-90 nL sample per well in 100% DMSO dispensed using a Labcyte ECHO 550) were prepared in the BSL-2 laboratory with 5 μL in each well. Prepare by adding assay medium. The plate is transferred to a BSL-3 facility and a 25 μL aliquot of virus-inoculated cells (4000 Vero E6 cells/well) is added to each well in columns 3-22. Wells in columns 23-24 contain only virus-infected cells (no compound treatment). Prior to virus infection, add a 25 μL aliquot of cells to columns 1-2 of each plate to serve as a cell only (no virus) control. After incubating the plates for 72 hours at 37° C./5% CO ₂ and 90% humidity, 30 μL of Cell Titer-Glo (Promega) is added to each well. After incubation for 10 minutes at room temperature, read luminescence and measure cell viability using a Perkin Elmer Envision or BMG CLARIOstar plate reader. The raw data from each test well was normalized to the average signal of uninfected cells (average cells; 100% inhibition) and virus-infected cells only (average virus; 0% inhibition) and the percent inhibition of CPE was calculated using the following formula: Calculate: Percent inhibition = 100*(test compound-average virus)/(average cells-average virus). SARS CPE assays are performed under BSL-3 confinement, plates are sealed with transparent covers and surfaces are decontaminated before reading the luminescence.

Compound 1 was tested in a 10-point dose response (15 μM high concentration → 2-fold dilution) and obtained an IC ₅₀ of 120 nM for inhibition of SARS CoV-2 mediated cell killing. Compound 1 showed no general cytotoxic effects, with a CC50>30 μM.

Compound 2 was tested in a 10-point dose response (15 μM high concentration → 2-fold dilution) and obtained an IC ₅₀ of <20 nM for inhibition of SARS CoV-2 mediated cell killing. Compound 2 showed no general cytotoxic effects, with a CC50 of 482 nM.

Compound 3 was tested in a 10-point dose response (15 μM high concentration → 2-fold dilution) and obtained an IC ₅₀ of 36 nM for inhibition of SARS CoV-2 mediated cell killing. Compound 3 showed no general cytotoxic effects, with a CC50 of 1,964 μM.

Compound 4 was tested in a 10-point dose response (15 μM high concentration → 2-fold dilution) and obtained an IC ₅₀ of 109 nM for inhibition of SARS CoV-2 mediated cell killing. Compound 4 showed no general cytotoxic effects, with a CC50 of 2,764 μM.

SARS CoV-2 CPE assay for synergy in combination with remdesivir.
One or more other additional agents are tested in combination with remdesivir using the assay protocol of Example 5. Each drug is evaluated in a 10-point dose response (high concentration 15 μM → 2-fold dilution).

SARS CoV-2 CPE assay for synergy in combination with hydroxychloroquine.
One or more other additional agents are tested in combination with hydroxychloroquine (HCQ) using the assay protocol of Example 5. Each drug is evaluated in a 10-point dose response (high concentration 15 μM → 2-fold dilution).

SARS CoV-2 CPE reporter assay for antiviral activity.
Nanoluc reporter virus assay for SARS-CoV-2 in A549 lung epithelial cells (NLRVA) is used to assess anti-SARS CoV-2 activity in human lung epithelial cell lines. Cell viability is measured using Promega Cell Titer Glo. Viral replication is determined by the level of nanoluc luciferase enzyme activity measured with the Promega Nano-Glo® Luciferase Assay System 48 hours after inoculation of host cells. The assay determines the difference in nanoluc activity between infected and uninfected cells, and the variability of the assay is sufficient to yield a Z' factor >0.5. In a SARS CoV-2 NLRVA using A549 lung epithelial cells expressing ACE2, each compound was tested as a single agent or as a second antibody by six two-fold dilutions up to 0.04 μM at a maximum concentration of 2.5 μM. Compounds are tested in combination with viral agents over a 7-point concentration range (duplicate).

Compound 1 was tested in a 7-point dose response (2.5 μM high concentration → 2-fold dilution) and obtained an IC ₅₀ of 59 nM for inhibition of SARS CoV-2 mediated cell killing. Compound 1 showed no general cytotoxic effects, with a CC50 of 2 μM.

Compound 2 was tested in a 7-point dose response (2.5 μM high concentration → 2-fold dilution) and obtained an IC ₅₀ of <20 nM for inhibition of SARS CoV-2 mediated cell killing. Compound 2 showed no general cytotoxic effects, with a CC50 of 159 nM.

Compound 3 was tested in a 7-point dose response (2.5 μM high concentration → 2-fold dilution) and obtained an IC ₅₀ of <20 nM for inhibition of SARS CoV-2 mediated cell killing. Compound 3 showed no general cytotoxic effects, with a CC50 of 1,370 μM.

Compound 4 was tested in a 7-point dose response (2.5 μM high concentration → 2-fold dilution) and obtained an IC ₅₀ of 35 nM for inhibition of SARS CoV-2 mediated cell killing. Compound 4 showed no general cytotoxic effects, with a CC50 of 557 nM.

MERS Coronavirus CPE Assay for Antiviral Activity A cell-based assay is used to measure the cytopathic effect (CPE) of a virus infecting Vero E6 host cells. Host cells infected with a virus die as a result of the virus hijacking the cellular machinery for genome replication. CPE reduction assays indirectly monitor the effectiveness of antiviral agents acting through various molecular mechanisms by measuring host cell viability 3 days after virus inoculation. Antiviral compounds are identified as those that protect host cells from the cytopathic effects of viruses, thereby increasing survival.

Vero E6 cells selected for expression of the SARS CoV receptor (ACE2; angiotensin converting enzyme 2) are used for CPE assays. Cells were grown in MEM/10% HI FBS and harvested in MEM/1% PSG/2% HI FBS. Cells were infected with coronavirus EMC/2012 MERS by M. O. I. Batch inoculation at ~0.002 yields 5% cell viability 96 hours after infection. Assay plates (ARP; Corning 3712BC) predosed with test compounds (30-90 nL sample per well in 100% DMSO dispensed using a Labcyte ECHO 550) were prepared in the BSL-2 laboratory with 5 μL in each well. Prepare by adding assay medium. The plate is transferred to a BSL-3 facility and a 25 μL aliquot of virus-inoculated cells (4000 Vero E6 cells/well) is added to each well in columns 3-22. Wells in columns 23-24 contain only virus-infected cells (no compound treatment). Prior to virus infection, add a 25 μL aliquot of cells to columns 1-2 of each plate to serve as a cell only (no virus) control. After incubating the plates for 72 hours at 37° C./5% CO ₂ and 90% humidity, 30 μL of Cell Titer-Glo (Promega) is added to each well. After incubation for 10 minutes at room temperature, read luminescence and measure cell viability using a Perkin Elmer Envision or BMG CLARIOstar plate reader. The raw data from each test well was normalized to the average signal of uninfected cells (average cells; 100% inhibition) and virus-infected cells only (average virus; 0% inhibition) and the percent inhibition of CPE was calculated using the following formula: Calculate: Percent inhibition = 100*(test compound-average virus)/(average cells-average virus). SARS CPE assays are performed under BSL-3 confinement, plates are sealed with transparent covers and surfaces are decontaminated before reading the luminescence.

Hepatitis C (HCV genotype 1b) replicon assay for antiviral activity.
The HCV replicon antiviral evaluation assay tests the efficacy of compounds in six serial dilutions. This assay uses HCV replicon 1b (Con1 strain containing a luciferase reporter) in the Huh7 human hepatoma cell line. Human interferon alpha-2b (rIFNα-2b) is included in each run as a positive control compound. Briefly, replicon cells are plated at 5,000 cells/well in 96-well plates dedicated to analysis of cell number (cytotoxicity) or antiviral activity. The next day, the samples are diluted in assay medium and added to the appropriate wells. Cells are processed after 72 hours while cells are still subconfluent. Luciferase endpoint assays assess HCV replicon levels as replicon-derived Luc activity. Toxic concentrations of agents that reduce cell number are assessed by the CytoTox-1 Cell Proliferation Assay (Promega), a fluorometric assay of cell number (and cytotoxicity). If applicable, EC50 (concentration that inhibits HCV replicon by 50%), EC90 (concentration that inhibits HCV replicon by 90%), CC50 (concentration that decreases cell viability by 50%), CC90 (concentration that decreases cell viability by 90%) concentration) and SI (selectivity index: CC50/EC50 and CC90/EC90) values are derived.

PRVABC59 (Verocell) ZIKA CPE assay for antiviral activity.
Vero cells and PRVABC59 strain are used for the Zika virus cytoprotection assay. Briefly, virus and cells are mixed in the presence of test compound and incubated for 5 days. Virus is pre-titrated such that symmetric wells exhibit 85-95% loss of cell viability due to viral replication. Therefore, antiviral efficacy is evaluated as a function of cytoprotection. Cytoprotective effects and cytotoxicity of compounds are assessed by MTS (CellTiter® 96 reagent, Promega, Madison WI) reduction. The percentage reduction of viral cytopathic effect (CPE) is determined and reported; EC50 (concentration that inhibits 50% of virus-induced cytopathic effect), CC50 (concentration that results in 50% cell death) and calculated SI ( Selectivity index = CC50/EC50) is provided along with a graphical representation of the antiviral activity and cytotoxicity of the compound when the compound is tested in a dose-response manner. Each assay includes interferon-β as a positive control.

Cell Preparation Vero cells were cultured in Dulbecco's Minimum Essential Medium (DMEM with Glutamax, Gibco) supplemented with 10% fetal bovine serum (FBS) at a 1:10 split ratio for weeks using standard cell culture techniques. Subculture twice. Determination of total cell number and viability is performed using a hemocytometer and trypan blue dye exclusion. In order for cells to be used in assays, cell viability must be greater than 95%. Cells are seeded in 96-well tissue culture plates at a concentration of 1×10 ⁴ cells/well the day before the assay. Antiviral assays are performed in DMEM supplemented with glutamine and 2% low concentration FBS.

Virus Preparation The virus used in this assay is strain PRVABC59. ZIKV PRVABC59 strain was isolated in 2015 from human serum collected in Puerto Rico, obtained from the Centers for Disease Control and Prevention (CDC, Division of Vector-Borne Infectious Diseases, Fort Collins, Colorado), and used for generation of a stock virus pool. were grown in Vero cells for this purpose. For each assay, a pre-titrated aliquot of virus was removed from the freezer (-80°C), hydrated, resuspended, and diluted in tissue culture medium to ensure that the amount of virus added to each well was between 85 and 95 at 5 days postinfection. % of cell death.

Compound dilution format Evaluate the antiviral efficacy of the sample by performing triplicate measurements using 6 concentrations in half-log dilution to determine EC50 values and in duplicate to determine cytotoxicity. .

Cell Viability At the end of the assay (5 days post-infection), 15 μL of soluble tetrazolium-based MTS (CellTiter® 96 reagent, Promega) is added to each well. The microtiter plate is then incubated for 1-2 hours at 37°C/5% _CO2 . MTS is metabolized by mitochondrial enzymes of metabolically active cells to produce soluble colored formazan products. Using an adhesive plate sealer in place of the lid, each plate is read spectrophotometrically at 490/650 nm using a Molecular Devices SpectraMax i3 plate reader.

Data Analysis An in-house computer program is used to calculate percent cytopathic effect (CPE) reduction, cell viability, EC25, EC50, EC95, CC25, CC50, and CC95, as well as other indicators.

Equivalents Although specific embodiments have been discussed, the above specification is intended to be illustrative and not restrictive. Many variations of the embodiments will become apparent to those skilled in the art upon consideration of this specification. The full scope of what is disclosed should be determined by reference to the claims, full scope of equivalents, and the specification, as well as such modifications.

Unless otherwise indicated, all numbers expressing quantities of components, reaction conditions, etc. used in the specification and claims are to be understood as modified in all cases by the term "about". Should. Therefore, unless indicated to the contrary, the numerical parameters set forth herein and in the appended claims are approximations that may vary depending on the desired properties sought to be obtained.

Claims (57)

A method of alleviating or treating a viral infection in a patient in need thereof, comprising formula I:

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, to said patient, wherein:
R ¹ is selected from phenyl and monocyclic 5-6 membered heteroaryl, each of phenyl and monocyclic 5-6 membered heteroaryl being halogen, C ₁ -C ₆ alkyl, C ₃ -C ₄ cycloalkyl , C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, amino, N-C ₁ -C ₃ alkylamino and N,N-diC ₁ -C ₃ alkylamino optionally substituted with one or more substituents independently selected from;
R ² is selected from the group consisting of H, C ₁ -C ₃ haloalkyl, and C ₁ -C 3 alkyl; R ³ is selected from the group consisting of A, phenyl, and monocyclic heteroaryl, including phenyl and hetero each aryl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of R ⁴ , R ⁵ , R ⁶ , and R ⁷ ;
Each of R ⁴ , R ⁵ , R ⁶ , and R ⁷ is halogen, C ₁ -C ₆ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ - Independent from the group consisting of C ₆ haloalkoxy, azetidine, amino, N-C ₁ -C ₃ alkylamino, N,N-diC ₁ -C ₃ alkylamino, NHSO ₂ R ⁸ , SO ₂ R ⁹ , and hydroxy selected;
R ⁸ is selected from C ₁ -C ₃ haloalkyl and C ₁ -C ₃ alkyl;
Each R ⁹ is R ¹⁰ , C ₁ -C ₆ alkyl, amino, N-C ₁ -C ₃ alkylamino, N,N-diC ₁ -C ₃ alkylamino, and C ₁ -C ₃ alkoxyC ₁ - independently selected from the group consisting of C ₃ alkyl, each of C ₁ -C ₆ alkyl and C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl optionally substituted with one occurrence of R ¹⁰ ; each of ₁ -C ₆ alkyl and C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl is optionally substituted with one or more independent occurrences of halogen;
Each R ¹⁰ is independently selected from the group consisting of phenyl, benzyl, monocyclic heteroaryl, C ₃ -C ₆ cycloalkyl, and heterocyclyl, phenyl, benzyl, monocyclic heteroaryl, C ₃ -C ₆ each cycloalkyl, and heterocyclyl is optionally substituted with one or more occurrences of R ¹¹ ;
Each R ¹¹ is halogen, C ₁ -C ₃ haloalkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₃ alkyl, amino, N-C ₁ -C ₃ alkylamino, N,N-diC ₁ -C independently selected from the group consisting of _3- alkylamino, and C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl;
A is

And;
R ¹² is H, halogen, COR ¹³ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ cyanoalkyl, and C ₁ -C ₃ haloalkyl;
R ¹³ is from the group consisting of C ₁ -C ₃ alkoxy, N-C ₁ -C ₃ alkylamino, N,N-diC ₁ -C ₃ alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl Y is selected from the group consisting of _CH2 , S, SO, _SO2 , ^NR14 , ^NCOR9 , ^{NCOOR15 ,} _NSO2R9 ^, _NCOCH2R9 , O and a bond;
R ¹⁴ is selected from H, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl, C ₁ -C ₃ alkyl, and C ₃ -C ₆ cycloalkyl;
_R ¹⁵ is selected from R ¹⁰ _{, C 1} -C ₆ alkyl, and C _{1 -C 3} alkoxyC _{1 -C 3} alkyl _; is optionally substituted with one occurrence of R ¹⁰ and each of C ₁ -C ₆ alkyl and C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl is optionally substituted with one or more independent occurrences of halogen. optionally replaced;
A method in which Z is selected from CH and N. A method of inhibiting viral transmission, inhibiting viral entry, inhibiting viral replication, minimizing expression of viral proteins, or inhibiting viral release, comprising a compound of formula I or a pharmaceutical composition thereof. administering to a patient suffering from said virus a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; contacting an effective amount of a salt, stereoisomer, or tautomer with a virus-infected cell, wherein said compound of formula I:

In the formula,
R ¹ is selected from phenyl and monocyclic 5-6 membered heteroaryl, each of phenyl and monocyclic 5-6 membered heteroaryl being halogen, C ₁ -C ₆ alkyl, C ₃ -C ₄ cycloalkyl , C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, amino, N-C ₁ -C ₃ alkylamino and N,N-diC ₁ -C ₃ alkylamino optionally substituted with one or more substituents independently selected from;
R ² is selected from the group consisting of H, C ₁ -C ₃ haloalkyl, and C ₁ -C 3 alkyl; R ³ is selected from the group consisting of A, phenyl, and monocyclic heteroaryl, including phenyl and hetero each aryl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of R ⁴ , R ⁵ , R ⁶ , and R ⁷ ;
Each of R ⁴ , R ⁵ , R ⁶ , and R ⁷ is halogen, C ₁ -C ₆ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ - Independent from the group consisting of C ₆ haloalkoxy, azetidine, amino, N-C ₁ -C ₃ alkylamino, N,N-diC ₁ -C ₃ alkylamino, NHSO ₂ R ⁸ , SO ₂ R ⁹ , and hydroxy selected;
R ⁸ is selected from C ₁ -C ₃ haloalkyl and C ₁ -C ₃ alkyl;
Each R ⁹ is R ¹⁰ , C ₁ -C ₆ alkyl, amino, N-C ₁ -C ₃ alkylamino, N,N-diC ₁ -C ₃ alkylamino, and C ₁ -C ₃ alkoxyC ₁ - independently selected from the group consisting of C ₃ alkyl, each of C ₁ -C ₆ alkyl and C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl optionally substituted with one occurrence of R ¹⁰ ; each of ₁ -C ₆ alkyl and C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl is optionally substituted with one or more independent occurrences of halogen;
Each R ¹⁰ is independently selected from the group consisting of phenyl, benzyl, monocyclic heteroaryl, C ₃ -C ₆ cycloalkyl, and heterocyclyl, phenyl, benzyl, monocyclic heteroaryl, C ₃ -C ₆ each cycloalkyl, and heterocyclyl is optionally substituted with one or more occurrences of R ¹¹ ;
Each R ¹¹ is halogen, C ₁ -C ₃ haloalkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₃ alkyl, amino, N-C ₁ -C ₃ alkylamino, N,N-diC ₁ -C independently selected from the group consisting of _3- alkylamino, and C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl;
A is

And;
R ¹² is H, halogen, COR ¹³ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ cyanoalkyl, and C ₁ -C ₃ haloalkyl;
R ¹³ is from the group consisting of C ₁ -C ₃ alkoxy, N-C ₁ -C ₃ alkylamino, N,N-diC ₁ -C ₃ alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl selected; Y is selected from the group consisting of CH2 _, S, SO, _SO2 , ^NR14 , ^NCOR9 , ^NCOOR15 , _NSO2R9 , ^{NCOCH2R9 ,} O, and _a bond;
R ¹⁴ is selected from H, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl, C ₁ -C ₃ alkyl, and C ₃ -C ₆ cycloalkyl;
_R ¹⁵ is selected from R ¹⁰ _{, C 1} -C ₆ alkyl, and C _{1 -C 3} alkoxyC _{1 -C 3} alkyl _; is optionally substituted with one occurrence of R ¹⁰ and each of C ₁ -C ₆ alkyl and C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl is optionally substituted with one or more independent occurrences of halogen. optionally replaced;
A method in which Z is selected from CH and N. 3. The method of claim 1 or 2, wherein the viral infection is caused by a coronavirus. The viral infection is 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, HKU1 beta coronavirus, Middle East Respiratory Syndrome (MERS) coronavirus (MERS-CoV), Severe Acute Respiratory Syndrome (SARS) coronavirus. (SARS-CoV), and SARS-CoV-2. The method according to any one of claims 1 to 4, wherein the viral infection is caused by SARS-CoV-2. A method according to any one of claims 1 to 5, wherein the viral infection is COVID-19. 3. The method of claim 1 or 2, wherein the viral infection is caused by a positive RNA virus. 8. The method of claim 7, wherein the positive RNA virus is selected from the group consisting of the Coronaviridae virus, the Flaviviridae virus, and the Picornaviridae virus. 9. The method of claim 8, wherein the positive RNA virus is selected from the group consisting of rhinoviruses, flaviviruses, picornaviruses, and coronaviruses. 10. The positive RNA virus is selected from the group consisting of SARS CoV-1, SARS CoV-2, MERS, hepatitis C (HCV), rhinovirus, dengue virus, Zika virus, and West Nile virus. the method of. 10. The method of claim 9, wherein the positive RNA virus is a coronavirus. 10. The method of claim 3 or 9, wherein the coronavirus is selected from the group consisting of SARS CoV-1, SARS CoV-2 and MERS. 13. The method according to any one of claims 1 to 12, wherein the viral infection is a respiratory viral infection. 13. The method according to any one of claims 1 to 12, wherein the viral infection is an upper respiratory tract viral infection or a lower respiratory tract viral infection. 10. The method of claim 3 or 9, wherein the coronavirus is SARS CoV-2. 16. The method of any one of claims 1-15, further comprising administering to said patient a therapeutically effective amount of one or more other additional agents or compositions. 17. The method of claim 16, wherein the one or more other additional agents are selected from the group consisting of ribavirin, favipiravir, ST-193, oseltamivir, zanamivir, peramivir, danoprevir, ritonavir, and remdesivir. The one or more other additional agents may include protease inhibitors, fusion inhibitors, M2 proton channel blockers, polymerase inhibitors, 6-endonuclease inhibitors, neuraminidase inhibitors, reverse transcriptase inhibitors, aciclovir ), acyclovir, protease inhibitors, arbidol, atazanavir, atripla, boceprevir, cidofovir, combivir, darunavir, docosanol, edoxudin, entry inhibitors, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet , phosphonet, ganciclovir, ivacitabine, immunovir, idoxuridine, imiquimod, inosine, integrase inhibitors, interferon, lopinavir, loviride, moloxidine, nexavir, nucleoside analogs, penciclovir, pleconaril, podophyllotoxin, ribavirin, tipranavir, 17. The method of claim 16, wherein the method is selected from the group consisting of trifluridine, tridivir, tromantadine, Truvada, valacyclovir, valganciclovir, vicriviroc, vidarabine, viramidine, and zodovudine. The one or more other additional agents include lamivudine, interferon alpha, VAP anti-idiotypic antibody, enfuvirtide, amantadine, rimantadine, pleconaril, aciclovir, zidovudine, fomivirsen, protease inhibitors, double-stranded RNA activation 17. The method of claim 16, wherein the method is selected from the group consisting of caspase oligomerizer (DRACO), rifampicin, zanamivir, oseltamivir, danoprevir, ritonavir, and remdesivir. The one or more other additional agents include quinine (optionally in combination with clindamycin), chloroquine, amodiaquine, artemisinin and its derivatives, doxycycline, pyrimethamine, mefloquine, halofantrine, hydroxychloroquine, eflornithine, nitazoxanide. , ornidazole, paromomycin, pentamidine, primaquine, pyrimethamine, proguanil (optionally in combination with atovaquone), sulfonamides, tafenoquine, tinidazole and PPT1 inhibitors. 17. The method of claim 16, wherein the one or more other additional agents are RNA polymerase inhibitors. 22. The method of claim 21, wherein the RNA polymerase inhibitor is remdesivir. The one or more other additional agents may include a TMPRSS protease inhibitor, a lysosome blocker, a PIKfyve inhibitor, an anti-SARSCOV-2 antibody, a cocktail of anti-SARSCOV-2 antibodies, an anti-inflammatory agent, an anti-TRIF agent, a histamine H1/ 17. The method of claim 16, wherein the method is selected from the group consisting of H2 blockers, steroids, anticoagulants, complement targeting agents, statins, and ACE inhibitors. 24. The method of claim 23, wherein the TMPRSS protease inhibitor is selected from the group consisting of a TMPRSS4 inhibitor, a TMPRSS11A inhibitor, a TMPRSS11D inhibitor, a TMPRSS11E1 inhibitor, and a TMPRSS2 inhibitor. 25. The method of claim 23 or 24, wherein the TMPRSS protease inhibitor is a TMRSS2 protease inhibitor. 25. The method according to any one of claims 22 to 24, wherein the TMRESS-2 protease inhibitor is selected from camostat and nafamostat. 24. The method of claim 23, wherein the anti-SARSCOV-2 antibody is selected from LY-CoV555 (bamlanivimab) and LY-CoV016 (etesevimab). 24. The method of claim 23, wherein the cocktail of anti-SARS COV-2 antibodies is REGN-COV2. 24. The method of claim 23, wherein the anti-inflammatory drug is an IL-6 antagonist. 24. The method of claim 23, wherein the steroid is dexamethasone. 24. The method of claim 23, wherein the anticoagulant is low molecular weight heparin. 24. The method of claim 23, wherein the complement targeting agent is eculizumab. 23. The method of claim 22, wherein the statin is selected from the group consisting of atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. 24. The method of claim 23, wherein the ACE inhibitor is selected from the group consisting of benazepril, captopril enalapril/enalaprilat, fosinopril, lisinopril moexipril, perindopril quinapril, and ramipril. The one or more other additional agents are remdesivir, camostat, nafamostat, hydroxychloroquine, chloroquine, apilimod, LY-CoV555 (bamlanivimab), LY-CoV016 (etesevimab), REGN-COV2, tocilizumab, siltuximab, sarilumab, Olokizumab, BMS -945429, Silkumab, Clazakizumab, Adarim Mab, Infriximab, Eternel Second, Gorim Mab, Celtorizumab, Fiza Tijin, Nizachidine, Lanitidine, Lanitidine, Dexametazon, Low Molecular weight Hepaline, Eclizmab, Atle Bathtachin Fullbastatin, lobastatin, pita bastatin, plahattatin, rosbastatin, synbostatin , benazepril, captopril enalapril/enalaprilat, fosinopril, lisinopril moexipril, perindopril quinapril, and ramipril. 17. The method of claim 16, wherein the one or more other additional agents are selected from the group consisting of ABL inhibitors and JAK inhibitors. 37. The method of claim 36, wherein the ABL inhibitor is selected from the group consisting of imatinib, dasatinib, and ponatinib. 37. The method of claim 36, wherein the JAK inhibitor is selected from the group consisting of baricitinib, ruxolitinib, tofacitinib, and upadacitinib. 39. The method of any one of claims 1-38, wherein said compound is administered orally to said patient. 39. The method of any one of claims 1-38, wherein said compound is administered parenterally to said patient. A method of treating a coronavirus infection in a patient in need thereof, comprising:

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, to said patient, wherein:
R ¹ is selected from phenyl and monocyclic 5-6 membered heteroaryl, each of phenyl and monocyclic 5-6 membered heteroaryl being halogen, C ₁ -C ₆ alkyl, C ₃ -C ₄ cycloalkyl , C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, amino, N-C ₁ -C ₃ alkylamino and N,N-diC ₁ -C ₃ alkylamino optionally substituted with one or more substituents independently selected from;
R ² is selected from the group consisting of H, C ₁ -C ₃ haloalkyl, and C ₁ -C 3 alkyl; R ³ is selected from the group consisting of A, phenyl, and monocyclic heteroaryl, including phenyl and hetero each aryl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of R ⁴ , R ⁵ , R ⁶ , and R ⁷ ;
Each of R ⁴ , R ⁵ , R ⁶ , and R ⁷ is halogen, C ₁ -C ₆ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ - Independent from the group consisting of C ₆ haloalkoxy, azetidine, amino, N-C ₁ -C ₃ alkylamino, N,N-diC ₁ -C ₃ alkylamino, NHSO ₂ R ⁸ , SO ₂ R ⁹ , and hydroxy selected;
R ⁸ is selected from C ₁ -C ₃ haloalkyl and C ₁ -C ₃ alkyl;
Each R ⁹ is R ¹⁰ , C ₁ -C ₆ alkyl, amino, N-C ₁ -C ₃ alkylamino, N,N-diC ₁ -C ₃ alkylamino, and C ₁ -C ₃ alkoxyC ₁ - independently selected from the group consisting of C ₃ alkyl, each of C ₁ -C ₆ alkyl and C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl optionally substituted with one occurrence of R ¹⁰ ; each of ₁ -C ₆ alkyl and C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl is optionally substituted with one or more independent occurrences of halogen;
Each R ¹⁰ is independently selected from the group consisting of phenyl, benzyl, monocyclic heteroaryl, C ₃ -C ₆ cycloalkyl, and heterocyclyl, phenyl, benzyl, monocyclic heteroaryl, C ₃ -C ₆ each cycloalkyl, and heterocyclyl is optionally substituted with one or more occurrences of R ¹¹ ;
Each R ¹¹ is halogen, C ₁ -C ₃ haloalkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₃ alkyl, amino, N-C ₁ -C ₃ alkylamino, N,N-diC ₁ -C independently selected from the group consisting of _3- alkylamino, and C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl;
A is

And;
R ¹² is H, halogen, COR ¹³ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ cyanoalkyl, and C ₁ -C ₃ haloalkyl;
R ¹³ is from the group consisting of C ₁ -C ₃ alkoxy, N-C ₁ -C ₃ alkylamino, N,N-diC ₁ -C ₃ alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl selected; Y is selected from the group consisting of CH2 _, S, SO, _SO2 , ^NR14 , ^NCOR9 , ^NCOOR15 , _NSO2R9 , ^{NCOCH2R9 ,} O, and _a bond;
R ¹⁴ is selected from H, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl, C ₁ -C ₃ alkyl, and C ₃ -C ₆ cycloalkyl;
_R ¹⁵ is selected from R ¹⁰ _{, C 1} -C ₆ alkyl, and C _{1 -C 3} alkoxyC _{1 -C 3} alkyl _; is optionally substituted with one occurrence of R ¹⁰ and each of C ₁ -C ₆ alkyl and C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl is optionally substituted with one or more independent occurrences of halogen. optionally replaced;
A method in which Z is selected from CH and N. 42. The method of claim 41, wherein the Coronaviridae infection is caused by a coronavirus. 43. The method of any one of claims 41 or 42, wherein the Coronaviridae infection is caused by SARS-CoV-2. 44. The method according to any one of claims 41 to 43, wherein the Coronaviridae infectious disease is COVID-19. The coronavirus is 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, HKU1 beta coronavirus, Middle East Respiratory Syndrome (MERS) coronavirus (MERS-CoV), Severe Acute Respiratory Syndrome (SARS) coronavirus. 45. The method of claim 44, wherein the method is selected from the group consisting of (SARS-CoV). 46. The method of claim 45, wherein the coronavirus is SARS-CoV-2. 47. The method of any one of claims 1-46, wherein the method prevents morbidity or mortality in the patient. 48. The method of any one of claims 1-47, wherein the method minimizes or prevents the need to hospitalize the patient or minimizes or prevents the need to connect the patient to a ventilator. . 49. The method of any preceding claim, wherein the method minimizes or prevents the need to admit the patient to an intensive care unit. 50. A method according to any preceding claim, wherein the method minimizes or prevents the need to connect a ventilator to the patient. The compound is 4-(2-anilinopyrimidin-4-yl)-6-(2-chlorophenyl)-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6 -(3-pyridyl)-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-(4-pyridyl)-1 H-pyridin-2-one; 4-( 2-anilinopyrimidin-4-yl)-6-morpholino-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6- [2-(trifluoromethyl)-1-piperidyl]-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[2-(trifluoromethyl)-1- piperidyl]-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl)morpholine-4- yl]-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1 H-pyridin-2- 6-[4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino] -4-pyridyl]-1 H-pyridin-2-one; 6-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidine-4 -yl)amino]-4-pyridyl]-1 H-pyridin-2-one; 4-[2-(oxazol-2-ylamino)-4-pyridyl]-6-[3-(trifluoromethyl)morpholine- 4-yl]-1 H-pyridin-2-one; 4-[2-[(2-methylthiazol-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl)morpholine- 4-yl]-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-phenyl ]-1 H-pyridin-2-one; 4-[2-[(2-methylpyrazol-3-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]-1 H -Pyridin-2-one; 4-[2-[(2-methylthiazol-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]-1 H-pyridine-2 -one; 6-(4-methyl-3-pyridyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1 H-pyridin-2-one; 4- [2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-3-pyridyl]-1 H-pyridin-2-one; 6-[ 1-Ethyl-3-(trifluoromethyl)pyrazol-4-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino4-pyridyl]-1 H-pyridin-2-one; 4 -[2-[(1-methylimidazol-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenylpyridin-2-one; 6-(2-chlorophenyl)-4- [2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1 H-pyridin-2-one; 1-methyl-2'-((2-methylpyrimidin-4-yl)amino )-6-(2-(trifluoromethyl)phenyl)-[4,4'-bipyridin]-2(1H)-one, and its pharmaceutically acceptable salts, stereoisomers, and tautomers 51. The method according to any one of claims 1 to 50, selected from the group consisting of. The compound is 4-(2-anilinopyrimidin-4-yl)-6-(2-chlorophenyl)-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6 -(3-pyridyl)-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-(4-pyridyl)-1 H-pyridin-2-one; 4-( 2-anilinopyrimidin-4-yl)-6-morpholino-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6- [2-(trifluoromethyl)-1-piperidyl]-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[2-(trifluoromethyl)-1- piperidyl]-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl)morpholine-4- yl]-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1 H-pyridin-2- 6-[4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino] -4-pyridyl]-1 H-pyridin-2-one; 6-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidine-4 -yl)amino]-4-pyridyl]-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-( trifluoromethyl)-phenyl]-1 H-pyridin-2-one; 6-(4-methyl-3-pyridyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4- pyridyl]-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-3-pyridyl ]-1 H-pyridin-2-one; 6-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino 4 -pyridyl]-1 H-pyridin-2-one; 6-(2-chlorophenyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1 H-pyridine- 2-one; 6-(3-cyclopropylmorpholin-4-yl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1 H-pyridin-2-one ;1-Methyl-2'-((2-methylpyrimidin-4-yl)amino)-6-(2-(trifluoromethyl)phenyl)-[4,4'-bipyridin]-2(1H)-one , and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof. The compound is 4-(2-anilinopyrimidin-4-yl)-6-(2-chlorophenyl)-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6 -(3-pyridyl)-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-(4-pyridyl)-1 H-pyridin-2-one 4-(2 -anilinopyrimidin-4-yl)-6-morpholino-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[ 2-(trifluoromethyl)-1-piperidyl]-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl ]-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl ]-1 H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1 H-pyridin-2-one ;6-[4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]- 4-pyridyl]-1 H-pyridin-2-one; 6-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidine-4- yl)amino]-4-pyridyl]-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(tri fluoromethyl)-phenyl]-1 H-pyridin-2-one; 6-(4-methyl-3-pyridyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl ]-1 H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-3-pyridyl] -1 H-pyridin-2-one; 6-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]- 4-pyridyl]-1 H-pyridin-2-one; 6-(2-chlorophenyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1 H-pyridine -2-one; 1-methyl-2'-((2-methylpyrimidin-4-yl)amino)-6-(2-(trifluoromethyl)phenyl)-[4,4'-bipyridine]-2( 51. The method according to any one of claims 1 to 50, selected from the group consisting of 1H)-one, and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof. 51. A compound according to any one of claims 1 to 50, wherein R ¹ is a monocyclic 5-6 membered heteroaryl. 55. A compound according to any one of claims 1-50 and claim 54, wherein R ² is selected from H and C ₁ -C ₃ alkyl. Claims 1-1, wherein R ³ is selected from phenyl and monocyclic heteroaryl, each of phenyl and monocyclic heteroaryl optionally substituted with one or more occurrences of C ₁ -C ₆ haloalkyl. 50 and a compound according to any one of claims 54-55. R ³ is

The compound according to any one of claims 1 to 50 and claims 54 to 56.